Il-2rgamma binding compounds

ABSTRACT

IL-2Rβ ligands and IL-2Rγc ligands and compounds comprising the ligands are disclosed. The ligands and compounds such as heterodimers and fusion proteins comprising the IL-2Rβ ligands and/or the IL-2Rγc ligands can be IL-2 receptor agonists.

This application is a continuation of U.S. application Ser. No.16/884,726, filed on May 27, 2020, now allowed, which is a continuationof U.S. application Ser. No. 16/531,989, filed on Aug. 5, 2019, issuedas U.S. Pat. No. 10,689,417, which claims benefit under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62/785,754, filed on Dec. 28,2018, and U.S. Provisional Application No. 62/715,097, filed on Aug. 6,2018, each of which is incorporated by reference in its entirety.

FIELD

The present disclosure relates to IL-2Rβ ligands, to IL-2Rγc ligands andto compounds having an IL-2Rβ ligand and/or an IL-2Rγc ligand. Compoundssuch as synthetic heterodimers and recombinant fusion proteinscomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand can be IL-2receptor agonists.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in XML format and is hereby incorporated byreference in its entirety. The XML copy, created on Dec. 3, 2022, isnamed 62AJ-000630US-362857 XML Sequence Listing Dec.-3-2022.

BACKGROUND

Recombinant human Interleukin-2 (IL-2) was one of the firstimmuno-oncology agents studied in the clinic and was approved by the FDAfor use against some particularly challenging cancers, melanoma andrenal carcinoma in the 1990s. IL-2 is effective, producing durableresponses in up to 10% of patients with these tumors, but its utility islimited by very serious, dose-limiting toxicities. In addition, theefficacy of IL-2 in directing T-cell-mediated anti-tumor response iscompromised by concurrent IL-2-driven upregulation of T-cell suppressivesystems. There has been a continuing search for strategies to reduce thetoxicity of IL-2 therapy, and to avoid the immunosuppressive limitationson anti-tumor activity. To date, modestly effective strategies have beendeveloped to control systemic exposure, and thus toxicity, of thispotent biologic. Elucidation of the complicated biology of IL-2 has ledto modifications of the natural IL-2 molecule to alter the balance oftumor toxicity and suppression. However, these approaches are limited bythe use of natural IL-2 as a template, thus retaining elements of theundesirable, structure-driven bioactivities of the parent molecule.

Crucial to its anti-tumor properties, IL-2 exerts potent stimulatoryeffects on NK and cytotoxic CD8+ T-cells. However, the anti-tumoreffects are paradoxically suppressed by IL-2-directed stimulation ofT-regulatory cells (Tregs), which effectively blunts the anti-tumorimmune response. This dual effect of IL-2 is largely controlled by thenature of the IL-2 receptor (IL-2R) subunits expressed on the variouscells responsible for immune homeostasis. IL-2 is recognized bycombinations of three receptor subunits, which are differentially andconditionally expressed on many types of immune cells. The two signalingsubunits, known as IL-2Rβ (β) and IL-2Rγ-common (γc), initiate signalingwhen brought into correctly-oriented apposition by binding to IL-2. IL-2binds to IL-2Rβγc with an affinity of about 1 nM to form an activeternary complex. Most immune cells express, at various levels, theIL-2Rβ and IL-2Rγc subunits. There is also a third, non-signaling IL-2Rsubunit, IL-2Rα (also known as CD25), which is expressed on a subset ofimmune cells, notably Tregs. The complex of IL-2Rαβγc has a very highaffinity for IL-2 (about 10 pM), and cells expressing all three subunitsare therefore much more sensitive to IL-2. A popular and well-supportedstrategy for improving the efficacy of IL-2 receptor agonists againsttumors involves engineering IL-2R selectivity to reduce the binding ofIL-2 to the IL-2Rα subunit while maintaining IL-2Rβγc binding andsignaling to favor infiltration and stimulation of cytotoxic effectorT-cells (Teff cells) over Tregs at tumor sites.

The cause of IL-2 toxicity in the clinical setting is less wellunderstood; but is thought to be the result of exaggerated peripheralimmuno-stimulation of IL-2Rβγc-expressing T-cells accompanied byexcessive release of inflammatory cytokines. Toxicity is induced by thefrequent administration of high doses of IL-2 required to sustainadequate tumor exposure because of the short half-life of the naturalcytokine.

Strategies to address the limitations of IL-2 as a usefulimmuno-oncology therapy utilize mutants, fusion proteins, orchemically-modified IL-2 to alter the complex biology of the immuneregulator. An example is a modified form of IL-2, decorated with 6 largecleavable polyethylene glycol (PEG) moieties that serve the dualpurposes of altering receptor subunit binding specificity and prolongingthe circulating half-life of a reversibly inactive prodrug of IL-2. Asthe prodrug systemically circulates, a cascade of PEG removal imparts acomplicated pharmacokinetic (PK) profile of variously-active andinactive forms of the cytokine, producing low sustained peripheralexposure to active IL-2 agonism, and thereby avoids the C_(max)-drivensevere side effects of high dose IL-2. The last two PEGs to be cleavedare located near the IL-2Rα binding site, interfering with IL-2Rαbinding, but allowing for IL-2Rβγc signaling, consequently favoringcytotoxic T-cell activity over the suppressive Treg activity. Thisyields a promising therapeutic molecule that addresses two principaldeficiencies of IL-2 as an anti-cancer therapeutic: (a) avoidingactivation of IL-2Rαβγc on Tregs, and (b) half-life extension of theIL-2Rβγc-activating compound. However, these effects are necessarilyintertwined and are difficult to optimize separately, as is oftenrequired during pre-clinical and clinical development. This limits theuse of a bioactive IL-2 protein as a starting point for impartingmultiple new properties.

SUMMARY

According to the present invention, an IL-2Rβ ligand exhibits a bindingaffinity (IC50) to the human IL-2Rβ subunit of less than 100 μM.

According to the present invention, an IL-2Rβ ligand comprises an aminoacid sequence selected from any one of SEQ ID NO: 1 to SEQ ID NO: 193,SEQ ID NO: 578 to SEQ ID NO: 903, SEQ ID NO: 1028 to SEQ ID NO: 1050,and SEQ ID NOS 1052-1064, and 1084.

According to the present invention, an IL-2Rγc ligand exhibits a bindingaffinity (IC50) to the human IL-2Rγc subunit of less than 100 μM.

According to the present invention, an IL-2Rγc ligand comprises an aminoacid sequence selected from any one of SEQ ID NO: 194 to SEQ ID NO: 267,SEQ ID NO: 904 to SEQ ID NO: 1027, and SEQ ID NOS 1065-1083.

According to the present invention, a compound comprises at least oneIL-2Rβ ligand according to the present invention and/or an IL-2Rγcligand according to the present invention.

According to the present invention, a pharmaceutical compositioncomprises an IL-2Rβ ligand according to the present invention and/or anIL-2Rγc ligand according to the present invention; a compound accordingto the present invention; or a combination thereof.

According to the present invention, methods of treating cancer in apatient comprise administering to a patient in need of such treatment, atherapeutically effective amount of a pharmaceutical compositionaccording to the present invention.

According to the present invention, methods of treating an autoimmunedisease in a patient comprise administering to a patient in need of suchtreatment, a therapeutically effective amount of a pharmaceuticalcomposition according to the present invention.

According to the present invention, methods include: methods ofscreening compounds for IL-2Rβ and/or IL-2Rγc activity; methods ofactivating the human IL-2 receptor; methods of treating a disease in apatient wherein the IL-2 receptor signaling pathway is associated withthe etiology of the disease; methods of treating a disease in a patientwherein activation of the IL-2 receptor is effective in treating thedisease; methods of treating a disease in a patient wherein inhibitionof the IL-2 receptor is effective in treating the disease; methods oftreating a disease in a patient, wherein cells expressing the IL-2Rβand/or IL-2Rγc subunit are associated with the etiology of the disease;methods of treating a disease in a patient, wherein cells expressing theIL-2Rγc subunit and/or the L-2Rγc subunit are associated with theetiology of the disease; methods of treating a disease in a patientwherein reducing the sensitivity of Treg cells to IL-2 is effective intreating the disease; methods of imaging cells expressing the IL-2Rβsubunit and/or the IL-2Rγc subunit; methods of diagnosing a disease in apatient wherein the disease is associated with cells expressing theIL-2Rβ subunit and/or the IL-2Rγc subunit; methods of targeting acompound to cells expressing the IL-2Rβ subunit and/or the IL-2Rγcsubunit; and methods of delivering a cytotoxic compound to cellsexpressing the the IL-2Rβ subunit and/or IL-2Rγc subunit.

According to the present invention, a binding site of the IL-2Rβsubunit, wherein the group of IL-2Rβ ligands having amino acid sequencesof SEQ ID NOS: 1-163, 164-182, 578-808, 1028-1042, 1052-1060, and 1084,competitively bind to the binding site with each of the other IL-2Rβligands within the group; an IL-2Rβ ligand having amino acid sequence ofSEQ ID NO: 1041 does not compete for binding to the binding site withthe group of IL-2Rβ ligands; and IL-2 does not compete for binding tothe binding site with the group of IL-2Rβ ligands.

According to the present invention, a binding site of the IL-2Rγcsubunit, wherein the group of IL-2Rγc ligands having amino acidsequences of SEQ ID NOS: 194-210, 904-913, 211-233, 914-920, 234-245,246-254, 921-922, 265-267, 932-940, and 1065-1082, competitively bind tothe binding site with each of the other IL-2Rγc ligands within thegroup; an IL-2Rγc ligand having amino acid sequence of SEQ ID NO: 948does not compete for binding to the binding site with the group ofIL-2Rγc ligands; and IL-2 does not compete for binding to the bindingsite with the group of IL-2Rγc ligands.

Reference is now made to certain compounds and methods. The disclosedembodiments are not intended to be limiting of the claims. To thecontrary, the claims are intended to cover all alternatives,modifications, and equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings described herein are for illustration purposes only. Thedrawings are not intended to limit the scope of the present disclosure.

FIG. 1 shows STAT5 phosphorylation in NK-92 cells by IL-2Rβγc agonistsaccording to the present disclosure by Western Blot analysis.

FIG. 2A shows STAT5 phosphorylation in TF-1 cells by IL-2Rβγc agonistsaccording to the present disclosure by Western Blot analysis.

FIG. 2B shows RT-qPCR gene expression profiling comparing severaltransfected TF-1 cell populations.

FIG. 3 shows activation of STAT5, ERK1/2 and AKT in NK-92 cells byIL-2Rβγc agonists according to the present disclosure by Western Blotanalysis.

FIG. 4A shows STAT5 phosphorylation in NK-92 cells by IL-2Rβγc agonistsaccording to the present disclosure by Western Blot analysis.

FIG. 4B shows pSTAT5 dose response curves in NK-92 cells by the IL-2Rβγcagonists evaluated in FIG. 4A.

FIGS. 5A-5C show the results of an NK-92 proliferation assay usingIL-2Rβγc agonists according to the present disclosure (FIG. 5A), byrhIL-2 (FIG. 5B), and as an overlay comparison (FIG. 5C).

FIG. 6 shows the ELISA signal for various phage binding at pH 6.0 and pH7.5.

FIG. 7 show the ELISA signal for a phage exhibiting pH-dependent bindingcompared to a non-pH-dependent clone that exhibited a similar bindingaffinity at pH 6.0 and pH 7.5.

FIGS. 8A-8B show phage binding IC₅₀ curves for a non-pH-independentclone (FIG. 8A) and a pH-dependent phage (FIG. 8B) at pH 6.0 and pH 7.5.

FIGS. 9A-9B shows IC₅₀ curves for peptide binding to IL-2Rβ-Fc for anon-pH-independent clone (FIG. 9A) and for a peptide from screening thatexhibited pH-dependent binding (FIG. 9B).

FIG. 10 shows STAT5 phosphorylation in NK-92 cells by a heterodimericIL-2Rβγc agonist provided by the present disclosure.

DETAILED DESCRIPTION

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a moiety or substituent. For example,—CONH₂ is attached through the carbon atom and —X¹—X²-denotes aminoacids X¹ and X² covalently bonded through a single bond.

“Alkyl” refers to a saturated or unsaturated, branched, orstraight-chain, monovalent hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkene,or alkyne. Examples of alkyl groups include methyl; ethyls such asethanyl, ethenyl, and ethynyl; propyls such as propan-1-yl, propan-2-yl,prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, but-1-en-1-yl,but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, but-1-yn-1-yl, but-1-yn-3-yl,but-3-yn-1-yl, etc.; and the like. The term “alkyl” is specificallyintended to include groups having any degree or level of saturation,i.e., groups having exclusively carbon-carbon single bonds, groupshaving one or more carbon-carbon double bonds, groups having one or morecarbon-carbon triple bonds, and groups having combinations ofcarbon-carbon single, double, and triple bonds. Where a specific levelof saturation is intended, the terms alkanyl, alkenyl, and alkynyl areused. In certain embodiments, an alkyl group is C₁₋₆ alkyl, C₁₋₅ alkyl,C₁₋₄ alkyl, C₁₋₃ alkyl, and in certain embodiments, ethyl or methyl.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylradical. In certain embodiments, a cycloalkyl group is C₃₄ cycloalkyl,C₃₋₅ cycloalkyl, C₅₋₆ cycloalkyl, cyclopropyl, cyclopentyl, and incertain embodiments, cyclohexyl. In certain embodiments, cycloalkyl isselected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“Heterocycloalkyl” by itself or as part of another substituent refers toa saturated or unsaturated cyclic alkyl radical in which one or morecarbon atoms (and certain associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom; or to a parent aromaticring system in which one or more carbon atoms (and certain associatedhydrogen atoms) are independently replaced with the same or differentheteroatom such that the ring system violates the Hückel-rule. Examplesof heteroatoms to replace the carbon atom(s) include N, P, O, S, and Si.Examples of heterocycloalkyl groups include groups derived fromepoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like. Incertain embodiments, heterocycloalkyl is C₅ heterocycloalkyl and isselected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,imidazolidinyl, oxazolidinyl, thiazolidinyl, doxolanyl, and dithiolanyl.In certain embodiments, heterocycloalkyl is C₆ heterocycloalkyl and isselected from piperidinyl, tetrahydropyranyl, piperizinyl, oxazinyl,dithianyl, and dioxanyl. In certain embodiments a heterocycloalkyl groupis C₄ heterocycloalkyl, C₃₋₅ heterocycloalkyl, C₅₋₆ heterocycloalkyl,and in certain embodiments, C₅ heterocycloalkyl or C₆ heterocycloalkyl.In certain embodiments of heterocycloalkyl, the heteroatomic group isselected from —O—, —S—, —NH—, —N(—CH₃)—, —SO—, and —SO₂—, in certainembodiments, the heteroatomic group is selected from —O— and —NH—, andin certain embodiments the heteroatomic group is —O— or —NH—.

“Agonist” refers to a biologically active ligand which binds to itscomplementary biologically active receptor or subunit(s) and activatesthe receptor to cause a biological response mediated by the receptor, orto enhance a preexisting biological activity mediated by the receptor.

“Affinity” refers to the strength of the binding interaction between asingle biomolecule to its ligand/binding partner. Affinity is expressedas the IC₅₀.

“Antagonist” refers to a biologically active ligand or compound thatbinds to its complementary receptor or subunit(s) and blocks or reducesa biological response of the receptor.

Amino acid residues are abbreviated as follows: alanine is Ala or A;arginine is Arg is R; asparagine is Asn or N; aspartic acid is Asp or D;cysteine is Cys or C; glutamic acid is Glu or E; glutamine is Gln or Q;glycine is Gly or G; histidine is His or H; isoleucine is Ile or I;leucine is Leu or L; lysine is Lys or K; methionine is Met or M;phenylalanine is Phe or F; proline is Pro or P; serine is Ser or S;threonine is Thr or T; tryptophan is Trp or W; tyrosine is Tyr or Y; andvaline is Val or V.

“Non-natural amino acids” include, for example, β-amino acids,homo-amino acids, proline and pyruvic acid derivatives, histidinederivatives with alkyl or heteroatom moieties attached to the imidazolering, amino acids with pyridine-containing side chains, 3-substitutedalanine derivatives, glycine derivatives, ring-substituted phenylalanineand tyrosine derivatives, and N-methyl amino acids.

Amino acids having a large hydrophobic side chain include isoleucine(I), leucine (L), methionine (M), valine (V), phenylalanine (F),tyrosine (Y), and tryptophan (W).

Amino acids having a small hydrophobic side chain include alanine (A),glycine (G), proline (P), serine (S), and threonine (T).

Amino acids having a basic side chain include arginine (R), lysine (K),and histidine (H).

Amino acids having an acidic side chain include aspartate (D) andglutamate (E).

Amino acids having a polar/neutral side chain include histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), and tyrosine(Y).

Amino acids having an aromatic side chain include phenylalanine (F),histidine (H), tryptophan (W), and tyrosine (Y).

Amino acids having a hydroxyl side chain include serine (S), threonine(T), and tyrosine (Y).

“Conservative amino acid substitution” means that amino acids withineach of the following groups can be substituted with another amino acidwithin the group: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), andthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), and tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) and glutamate (E);amino acids comprising a polar-neutral side chain comprising histidine(H), asparagine (N), glutamine (Q), serine (S), threonine (T), andtyrosine (Y); amino acids having a basic side chain comprising arginine(R), lysine (K), and histidine (H); amino acids having a largehydrophobic side chain comprising isoleucine (I), leucine (L),methionine (M), valine (V), phenylalanine (F), tyrosine (Y), andtryptophan (W)); and amino acids having an aromatic side chaincomprising phenylalanine (F), histidine (H), tryptophan (W), andtyrosine (Y).

“PEG,” “polyethylene glycol” and “poly(ethylene glycol)” refer to anynonpeptidic water-soluble poly(ethylene oxide). PEGs can comprise astructure —(OCH₂CH₂)_(n)— where n is, for example, an integer from 1 to4,000. A PEG can also include moieties such as—CH₂CH₂—O(CH₂CH₂O)_(n)—CH₂CH₂— and/or —(OCH₂CH₂)_(n)O— moieties,depending upon whether or not the terminal oxygens have been displaced,e.g., during a synthetic transformation. A PEG can be capped with asuitable end group. At least 50% of the repeating subunits of a PEG canhave the structure —CH₂CH₂—. A PEG can have any suitable molecularweight, structure, and/or geometry such as branched, linear, forked, ormultifunctional.

Molecular weight in the context of a polymer refers to the numberaverage molecular weight as determined by gel permeation chromatographyusing a polystyrene standard. A polymer can have a polydispersity index(i.e., number average molecular weight and weight average molecularweight of the polymers are not equal), for example, less than 1.2, lessthan 1.15, less than 1.10, less than 1.05, or less than 1.03.

A linker refers to a moiety that binds at least one IL-2R ligand such asan IL-2Rα ligand, an IL-2Rβ ligand, and/or an IL-2Rγc ligand. A linkercan bind to another IL-2R ligand which can be the same IL-2R ligand or adifferent IL-2R ligand. A linker can also bind to one or more additionalmoieties that provide a desired physiological function. A linker can bedivalent or multivalent. A linker can be hydrolytically stable or mayinclude a physiologically hydrolyzable or enzymatically degradablelinkage. A linker can bind IL-2R ligands to form dimers, trimers, orhigher order multi-ligand peptides (heteromers) and compounds.

A “physiologically cleavable” or “hydrolyzable” or “degradable” bond isa bond that reacts with water (i.e., is hydrolyzed) under physiologicalconditions. The tendency of a bond to hydrolyze in water will depend notonly on the general type of linkage connecting two central atoms butalso on the substituents attached to these central atoms. Suitablehydrolytically unstable or weak linkages include but are not limited tocarboxylate ester, phosphate ester, anhydrides, acetals, ketals,acyloxyalkyl ether, imines, orthoesters, peptides and oligonucleotides.

An “enzymatically degradable linkage” means a linkage that can bedegraded or cleaved by one or more enzymes.

A “hydrolytically stable” linkage or bond refers to a chemical bond,such as a covalent bond, that is substantially stable in water such thatthe chemical bond does not undergo hydrolysis under physiologicalconditions to any appreciable extent over an extended period of time.Examples of hydrolytically stable linkages include, but are not limitedto, the following: carbon-carbon bonds (e.g., in aliphatic chains),ethers, amides, urethanes, and the like. Generally, a hydrolyticallystable linkage is one that exhibits a rate of hydrolysis of less thanabout 1% to 2% per day under physiological conditions.

An “IL-2Rα ligand” refers to a peptide capable of binding to the IL-2Rαsubunit of a mammalian IL-2 receptor with an affinity (IC₅₀) less than100 μM.

An “IL-2Rβ ligand” refers to a peptide capable of binding to the IL-2Rβsubunit of a mammalian IL-2 receptor with an affinity (IC₅₀) less than100 μM.

An “IL-2Rγc ligand” refers to a peptide capable of binding to theIL-2Rγc subunit of a mammalian IL-2 receptor with an affinity (IC₅₀)less than 100 μM.

A “human IL-2Rα ligand” comprises refers to a peptide capable of bindingto the IL-2Rα subunit of the human IL-2 receptor with an affinity (IC₅₀)less than 100 μM.

A “human IL-2Rβ ligand” refers to a peptide capable of binding to theIL-2Rβ subunit of the human IL-2 receptor with an affinity (IC₅₀) lessthan 100 μM.

A “human IL-2Rγc ligand” refers to a peptide capable of binding to theIL-2Rγc subunit of a mammalian IL-2 receptor with an affinity (IC₅₀)less than 100 μM.

A “human IL-2Rα ligand” comprises refers to a peptide capable of bindingto the IL-2Rα subunit of the human IL-2 receptor with an affinity (IC₅₀)less than 100 μM.

The “IL-2Rβ subunit” refers to the human (Homo sapiens) interleukin-2receptor subunit p precursor NCBI Reference Sequence NP_000689.1.

The “IL-2Rγc subunit” refers to the human (Homo sapiens) interleukin-2receptor subunit γ precursor NCBI Reference Sequence NP_000197.1.

An “IL-2R ligand fusion protein” refers to a protein made by recombinantDNA technology in which the translational reading frame of a ligand of amammalian IL-2 receptor is fused to that of another protein, i. e., IL-2receptor fusion partner, to produce a single recombinant polypeptide. AnIL-2R ligand fusion protein can comprise an IL-2Rβ ligand, an IL-2Rγcligand, or both an IL-2Rβ ligand and an IL-2Rγc ligand. An IL-2R ligandfusion protein can be produced as a disulfide-linked dimer, joinedtogether by disulfide bonds located in the hinge region. An IL-2R ligandfusion protein can include a peptide linker such as an amino acidsequence located between two proteins comprising a fusion protein, suchthat the linker peptide sequence is not derived from either partnerprotein. Peptide linkers can be incorporated into fusion proteins asspacers to promote proper protein folding and stability of the componentprotein moieties, to improve protein expression, and/or to enable betterbioactivity of the two fusion partners. Peptide linkers can be dividedinto the categories of unstructured flexible peptides or rigidstructured peptides.

Bioisosteres are atoms or molecules that fit the broadest definition forisosteres. The concept of bioisosterism is based on the concept thatsingle atom, groups, moieties, or whole molecules, which have chemicaland physical similarities produce similar biological effects. Abioisostere of a parent compound can still be recognized and accepted byits appropriate target, but its functions will be altered as compared tothe parent molecule. Parameters affected with bioisosteric replacementsinclude, for example, size, conformation, inductive and mesomericeffects, polarizability, capacity for electrostatic interactions, chargedistribution, H-bond formation capacity, pKa (acidity), solubility,hydrophobicity, lipophilicity, hydrophilicity, polarity, potency,selectivity, reactivity, or chemical and metabolic stability, ADME(absorption, distribution, metabolism, and excretion). Although commonin pharmaceuticals, carboxyl groups or carboxylic acid functional groups(—CO₂H) in a parent molecule may be replaced with a suitable surrogateor (bio)isostere to overcome chemical or biological shortcomings whileretaining the desired attributes of the parent molecule bearing one ormore carboxyl groups or carboxylic acid functional groups (—CO₂H).

“Isostere” or “isostere replacement” refers to any amino acid or otheranalog moiety having physiochemical and/or structural properties similarto a specified amino acid. An “isostere” or “suitable isostere” of anamino acid is another amino acid of the same class, wherein amino acidsbelong to the following classes based on the propensity of the sidechain to be in contact with polar solvent like water: hydrophobic (lowpropensity to be in contact with water), polar or charged (energeticallyfavorable contact with water). Examples of charged amino acid residuesinclude lysine (+), arginine (+), aspartate (−) and glutamate (−).Examples of polar amino acids include serine, threonine, asparagine,glutamine, histidine and tyrosine. Illustrative hydrophobic amino acidsinclude alanine, valine, leucine, isoleucine, proline, phenylalanine,tryptophan, cysteine and methionine. The amino acid glycine does nothave a side chain and is difficult to assign to one of the aboveclasses. However, glycine is often found at the surface of proteins,often within loops, providing high flexibility to these regions, and anisostere may have a similar feature. Proline has the opposite effect,providing rigidity to the protein structure by imposing certain torsionangles on the segment of the polypeptide chain. An isostere can be aderivative of an amino acid, e.g., a derivative having one or moremodified side chains as compared to the reference amino acid.

“Cyclized” refers to a reaction in which one part of a peptide orpolypeptide molecule becomes linked to another part of the peptide orpolypeptide molecule to form a closed ring, such as by forming adisulfide bridge or other similar bond, e.g., a lactam bond. Inparticular embodiments, peptide monomer compounds or monomer subunits ofpeptide dimer compounds described herein are cyclized via anintramolecular bond between two amino acid residues present in thepeptide monomer or monomer subunit.

“Patient” refers to a mammal, for example, a human.

“Peptide” refers to a polymer in which the monomers are α-amino acidsjoined together through amide bonds. A peptide can comprise, forexample, less than 100 amino acids, less than 50 amino acids, less than40 amino acids, less than 30 amino acids, or less than 20 amino acids. Apeptide can comprise naturally-occurring α-amino acids, non-naturallyoccurring amino acids, or a combination thereof.

In addition to peptides consisting only of naturally-occurring aminoacids, peptidomimetics or peptide analogs are also provided. Peptidemimetics that are structurally similar to therapeutically usefulpeptides may be used to produce an equivalent or enhanced therapeutic orprophylactic effect. Generally, peptidomimetics are structurally similarto a paradigm peptide, for example, a peptide that has a biological orpharmacological activity, such as a naturally-occurring receptor-bindingpeptide, but have one or more peptide linkages optionally replaced by alinkage such as —CH₂—NH—, —CH₂—S—, —CH₂—CH₂—, —CH═CH— (cis and trans),—COCH₂—, —CH(OH)CH₂—, and —CH₂SO—, by methods known in the art.

Systematic substitution of one or more amino acids of a consensussequence with a D-amino acid of the same type, such as D-lysine in placeof L-lysine, may be used to generate more stable peptides. In addition,constrained peptides comprising a consensus sequence or a substantiallyidentical consensus sequence variation may be generated by methods knownin the art; for example, by adding internal cysteine residues capable offorming intramolecular disulfide bridges which cyclize the peptide.

Synthetic or non-naturally occurring amino acids refer to amino acidswhich do not naturally occur in vivo but which, nevertheless, can beincorporated into the peptide ligands provided by the presentdisclosure. Suitable examples of synthetic amino acids include theD-α-amino acids of naturally occurring L-α-amino acid as well asnon-naturally occurring D- and L-α-amino acids represented by theformula H₂NCHR⁵COOH where R⁵ is C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈heterocycloalkyl; an aromatic residue of from 6 to 10 carbon atomsoptionally having from 1 to 3 substituents on the aromatic nucleusselected from the group consisting of hydroxyl, lower alkoxy, amino, andcarboxyl; -alkylene-Y where alkylene is an alkylene group of from 1 to 7carbon atoms and Y is selected from a hydroxyl, amino, cycloalkyl, andcycloalkenyl having from 3 to 7 carbon atoms; aryl of from 6 to 10carbon atoms, such as from 1 to 3 substituents on the aromatic nucleusselected from the group consisting of hydroxyl, lower alkoxy, amino andcarboxyl; heterocyclic of from 3 to 7 carbon atoms and 1 to 2heteroatoms selected from the group consisting of oxygen, sulfur, andnitrogen; —C(O)R² where R² is selected from the group consisting ofhydrogen, hydroxy, lower alkyl, lower alkoxy, and —NR³R⁴ where R³ and R⁴are independently selected from the group consisting of hydrogen andlower alkyl; —S(O)_(n)R⁶ where n is 1 or 2 and R² is C₁₋₄ alkyl and withthe proviso that R⁵ does not define a side chain of a naturallyoccurring amino acid.

Examples of other synthetic amino acids include amino acids wherein theamino group is separated from the carboxyl group by more than one carbonatom such as b-alanine, g-aminobutyric acid, and the like.

Examples of suitable synthetic amino acids include the D-amino acids ofnaturally occurring L-amino acids, L-1-naphthyl-alanine,L-2-naphthylalanine, L-cyclohexylalanine, L-2-amino isobutyric acid, thesulfoxide and sulfone derivatives of methionine, i.e.,HOOC—(H₂NCH)CH₂CH₂—S(O)_(n)R⁶, where n and R⁶ are as defined above aswell as the lower alkoxy derivative of methionine, i.e.,HOOC—(H₂NCH)CH₂CH₂OR⁶ where R⁶ is as defined above.

“Polypeptide” refers to a polymer in which the monomers are α-aminoacids joined together through amide bonds and comprising greater than100 amino acids.

“N-terminus” refers to the end of a peptide or polypeptide, such as anN-terminus of an IL-2Rβ ligand or an IL-2Rγc ligand, that bears an aminogroup in contrast to the carboxyl end bearing a carboxyl acid group.

“C-terminus” refers to the end of a peptide or polypeptide, such as aC-terminus of an IL-2Rβ ligand or an IL-2Rγc ligand, that bears acarboxylic acid group in contrast to the amino terminus bearing an aminogroup.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include acid addition salts, formed with inorganic acids andone or more protonable functional groups such as primary, secondary, ortertiary amines within the parent compound. Examples of inorganic acidsinclude hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. In certain embodiments the salts areformed with organic acids such as acetic acid, propionic acid, hexanoicacid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lacticacid, malonic acid, succinic acid, malic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, andthe like. In certain embodiments, a salt is formed when one or moreacidic protons present in the parent compound are replaced by a metalion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminumion, or combinations thereof; or coordinates with an organic base suchas ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, andthe like. In certain embodiments, a pharmaceutically acceptable salt isthe hydrochloride salt. In certain embodiments, a pharmaceuticallyacceptable salt is the sodium salt. In certain embodiments where acompound has two or more ionizable groups, a pharmaceutically acceptablesalt comprises one or more counterions, such as a bi-salt, for example,a dihydrochloride salt.

The term “pharmaceutically acceptable salt” includes hydrates and othersolvates, as well as salts in crystalline or non-crystalline form. Wherea particular pharmaceutically acceptable salt is disclosed, it isunderstood that the particular salt (e.g., a hydrochloride salt) is anexample of a salt, and that other salts may be formed using techniquesknown to one of skill in the art. Additionally, one of skill in the artwould be able to convert the pharmaceutically acceptable salt to thecorresponding compound, free base and/or free acid, using techniquesgenerally known in the art. See also: Stahl and Wermuth, C. G.(Editors), Handbook of Pharmaceutical Salts, Wiley-VCH, Weinheim,Germany, 2008.

“Pharmaceutically acceptable vehicle” refers to a pharmaceuticallyacceptable diluent, a pharmaceutically acceptable adjuvant, apharmaceutically acceptable excipient, a pharmaceutically acceptablecarrier, or a combination of any of the foregoing with which a compoundprovided by the present disclosure may be administered to a patient andwhich does not destroy the pharmacological activity thereof and which isnon-toxic when administered in doses sufficient to provide atherapeutically effective amount of the compound.

“Solvate” refers to a molecular complex of a compound with one or moresolvent molecules in a stoichiometric or non-stoichiometric amount. Suchsolvent molecules are those commonly used in the pharmaceutical arts,which are known to be innocuous to a patient, e.g., water, ethanol, andthe like. A molecular complex of a compound or moiety of a compound anda solvent can be stabilized by non-covalent intra-molecular forces suchas, for example, electrostatic forces, van der Waals forces, or hydrogenbonds. The term “hydrate” refers to a solvate in which the one or moresolvent molecules is water.

“Pharmaceutical composition” refers to an IL-2R binding compoundprovided by the present disclosure or a pharmaceutically acceptable saltthereof and at least one pharmaceutically acceptable vehicle with whichthe compound or a pharmaceutically acceptable salt thereof isadministered to a patient. Pharmaceutically acceptable vehicles areknown in the art.

“Disease” refers to a disease, disorder, condition, or symptom of any ofthe foregoing.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease). In some embodiments, “preventing” or“prevention” refers to reducing symptoms of the disease by taking thecompound in a preventative fashion. The application of a therapeutic forpreventing or prevention of a disease of disorder is known as‘prophylaxis.’

“Prodrug” refers to a derivative of a therapeutic compound that requiresa transformation within the body to release the active therapeuticcompound. Prodrugs are frequently, although not necessarily,pharmacologically inactive until converted to the parent drug.

“Promoiety” refers to a group bonded to a therapeutic compound,typically to a functional group of the therapeutic compound, via bond(s)that are cleavable under specified conditions of use. The bond(s)between the drug and promoiety may be cleaved by enzymatic ornon-enzymatic means. Under the conditions of use, for example followingadministration to a patient, the bond(s) between the therapeuticcompound and the promoiety may be cleaved to release the parenttherapeutic compound. The cleavage of the promoiety may proceedspontaneously, such as via a hydrolysis reaction, or it may be catalyzedor induced by another agent, such as by an enzyme, by light, by acid, orby a change of or exposure to a physical or environmental parameter,such as a change of temperature, pH, etc. The agent may be endogenous tothe conditions of use, such as an enzyme present in the systemiccirculation of a patient to which the prodrug is administered or theacidic conditions of the stomach or the agent may be suppliedexogenously.

“Substantially” means, for example, greater than 90%, greater than 95%,greater than 98%, or greater than 99%.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease, or at leastone of the clinical symptoms of a disease, is sufficient to treat thedisease or symptom thereof. The “therapeutically effective amount” mayvary depending, for example, on the compound, the disease and/orsymptoms of the disease, severity of the disease and/or symptoms of thedisease or disorder, the age, weight, and/or health of the patient to betreated, and the judgment of the prescribing physician. An appropriateamount in any given instance may be ascertained by those skilled in theart or capable of determination by routine experimentation.

“Therapeutically effective dose” refers to a dose that provideseffective treatment of a disease or disorder in a patient. Atherapeutically effective dose may vary from compound to compound, andfrom patient to patient, and may depend upon factors such as thecondition of the patient and the route of delivery. A therapeuticallyeffective dose may be determined in accordance with routinepharmacological procedures known to those skilled in the art.

“Treating” or “treatment” of a disease refers to arresting orameliorating a disease or at least one of the clinical symptoms of adisease or disorder, reducing the risk of acquiring a disease or atleast one of the clinical symptoms of a disease, reducing thedevelopment of a disease or at least one of the clinical symptoms of thedisease or reducing the risk of developing a disease or at least one ofthe clinical symptoms of a disease. “Treating” or “treatment” alsorefers to inhibiting the disease, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, and to inhibiting atleast one physical parameter or manifestation that may or may not bediscernible to the patient. In certain embodiments, “treating” or“treatment” refers to delaying the onset of the disease or at least oneor more symptoms thereof in a patient who may be exposed to orpredisposed to a disease or disorder even though that patient does notyet experience or display symptoms of the disease.

“Tregs” or “Treg cells” refer to regulatory T cells. Regulatory T cellsare a class of T cells that suppress the activity of other immune cellsand are defined using flow cytometry by the cell marker phenotypesCD4+/CD25+/FOXP3+, CD4+CD25+CD127lo, or CD4+/CD25+/FOXP3+/CD127lo.Because FOXP3 is an intracellular protein and requires cell fixation andpermeablization for staining, the cell surface phenotypeCD4+CD25+CD127lo- can be used for defining live Tregs. Tregs alsoinclude various Treg subclasses, such as tTregs (thymus-derived) andpTregs (peripherally-derived, differentiated from naive T cells in theperiphery). All Tregs express the IL-2Rαβγ receptor, do not produce IL-2and are dependent on IL-2 for growth. A person skilled in the art willrecognize that Tregs will be more potently activated by anIL-2Rαβγc-biased agonist.

“CD4+ T cells” are a type of lymphocyte that functions to coordinate theimmune response by stimulating other immune cells such as macrophages, Blymphocytes (B cells), CD8 lymphocytes (CD8 cells) to fight infection.CD4+ T cells recognize peptides presented on MHC Class II molecules,which are found on antigen presenting cells.

“CD8+(cytotoxic) T cells” are generated in the thymus and express theT-cell receptor. Cytotoxic T cells express a dimeric co-receptor, CD8,which typically comprises one CD8α and one CD80 chain. CD8+ T cellsrecognize peptides presented by MHC Class 1 molecules found on allnucleated cells. The CD8 heterodimer binds to a conservative portion ofMHC Class 1 during T cell/antigen presenting cell interactions. CD8+T-cells (cytotoxic T lymphocytes, or CTLs) are important for immunedefense against intracellular pathogens including viruses and bacteria,and for tumor surveillance.

“NK (natural killer) cells” are lymphocytes in the same family as T andB cells and, as cells of the innate immune system, are classified asgroup I innate lymphocytes (ILCs). NK cells respond to a wide variety ofpathological challenges including killing virally infected cells anddetecting and controlling early signs of cancer.

“Functional activation of T cells” is defined as an IL-2-mediatedresponse in T cells. Assays for functional activation of T cells includestimulation of pSTAT5, Treg cell proliferation or markers ofproliferation (such as Ki67), change in immune cell type ratios, andstimulation of the levels of T-cell effector proteins.

Reference is now made in detail to certain embodiments of compounds,compositions, and methods. The disclosed embodiments are not intended tobe limiting of the claims. To the contrary, the claims are intended tocover all alternatives, modifications, and equivalents.

Interleukin-2 (IL-2) plays a crucial role in regulating immune responsesand maintaining peripheral self-tolerance by having bothimmuno-stimulatory and immuno-regulatory functions. IL-2 acts primarilyas a T cell growth factor, essential for the proliferation and survivalof T cells as well as for the generation of effector and memory T cells.IL-2 is a four α-helical bundle cytokine that belongs to a family ofstructurally related cytokines that includes IL-4, IL-7, IL-9, IL-15,and IL-21. IL-2 is produced by activated CD4+ T cells in response toantigen stimulation and can also be produced by CD8+ T cells and innateimmune cells such as activated dendritic cells (DCs) and natural killer(NK) cells.

IL-2 binds to various forms of the IL-2 receptor (IL-2R), notably themonomeric, dimeric, and trimeric forms. Monomeric IL-2R consists of themembrane-associated IL-2Rα (CD25) chain, which also exists in a solubleform; however, it is not capable of inducing signaling events. Thetrimeric IL-2R consists of IL-2Rα, IL2Rβ (CD122), and IL-2Rγc, alsoknown as the common γ-chain (γc) or CD132 and is shared by all membersof the IL-2 cytokine family. Dimeric IL-2R comprises the IL-2Rγc andIL-2Rβ subunits. In contrast to monomeric IL-2R, both the dimeric andtrimeric IL-2 receptors lead to a downstream signaling cascade upon IL-2binding IL-2 binds with high affinity to the trimeric IL-2R but withlow-moderate affinity to the dimeric IL-2R, varying the sensitivity ofthe cell to IL-2 Additionally. IL-2 can bind to IL-2Rα expressed on thesurface of activated dendritic cells for trans presentation toneighboring cells including antigen-specific naïve T cells and NK cellsthat express both IL-2Rβ and IL-2Rγc subunits. This trans presentationof IL-2 has been shown to facilitate initial high affinity IL-2signaling, required early in the immune response to prime naïve T-cellsto produce IL-2.

IL-2 is first captured by IL2Rα, bringing about a conformational changeto IL-2, increasing its affinity for IL-2Rβ. Association of IL-2 withthe IL-2Rβγc induces the dimerization of the signaling motifs in thecytoplasmic tails of IL-2Rβ and IL-2Rγc leading to thephosphorylation/activation of the Janus kinases, JAK1 and JAK3, which inturn exert kinase activity on key tyrosine residues in the tail of theIL-2Rβ subunit.

Downstream signaling occurs via three major pathways, the JAK-STATpathway, the phosphoinositide 3-kinase (PI3K)-AKT pathway, and themitogen-activated protein kinase (MAPK) pathway. These pathwaysultimately result in the transcription of target genes that contributeto IL-2-dependent biological actions, through the recruitment of theadaptor protein She and the transcription factor STAT5. Target genes ofIL-2 signaling include cyclin D2, bcl-2, fasL, cd25 (encoding IL-2Rα),socs1-2, and the IL-2 silencing gene prdm1, which encodes for thetranscription factor, BLIMP1. The production of the negative regulatorof IL-2 BLIMP1 is essential for maintaining the balance between effectorT cells and Treg cells, which is crucial for immune homeostasis.

IL-2 plays a dual role in T cell activation by stimulating theproliferation and differentiation of T cells as well as by maintainingand expanding the population of immuno-suppressive Treg cells. Theconventional naïve CD4+ and CD8+ T cells express the dimeric IL-2R, andtherefore require a high concentration of IL-2 to induce their initialproliferation. Once activated, these T cells express the high-affinitytrimeric IL-2R, driving the differentiation of the T cells into eithereffector (Teff) or memory cells. This differentiation depends on thestrength and duration of the IL-2 signal.

During the primary expansion of CD8+ T cells in the presence oflow-moderate levels of IL-2, a subset of CD8+ T cells will differentiateinto memory T cells. The cells do this by downregulating CD25 andupregulating CD127 (IL-7R) and CD62 (L-selectin), which are crucialreceptors for secondary responses upon re-infection. During an acuteinfection, sustained high levels of IL-2 leads to a rapid up-regulationof CD25 and the differentiation of CD8+ cells into cytotoxic effectorcells. The upregulation induces an IL-2-driven expression of the deathreceptor fas and fasL, causing activation-induced cell death (AICD) uponpathogen clearance. For CD4+ T cells, the activation of STAT5 signalingby IL-2 influences their differentiation into multiple helper T cellpopulations, including Th1, Th2, and Th17 by regulating the expressionof the appropriate receptors for each response.

Homeostatic or background levels of IL-2 are essential for the survivaland function of Treg cells by maintaining the expression of FOXP3 andCD25. Treg cells naturally occur in the thymus and upon contact withself-peptides become activated. Additionally, Treg cells can begenerated by stimulation of conventional CD4+ T cells upon interactionwith antigens in peripheral lymphoid organs. Because Treg cells do notproduce IL-2, they are dependent on IL-2-producing cells such asconventional T cells. Additionally, due to their high expression ofIL-2Rα (CD25), Tregs are able to consume and limit the systemicconcentration of IL-2, ensuring the regulation of the immune balance. Inthe absence of IL-2, the number of Treg cells decreases and the numberof effector T cells increases, leading to an enhanced susceptibility toautoimmune and inflammatory disorders. Therefore, the unique activationof Treg cells at low levels of IL-2, which does not activate CD4+ orCD8+ T cells, has allowed for the development of IL-2 as a promisingtherapeutic in autoimmune and inflammatory diseases.

The production of IL-2 from both arms of the immune system highlightsthe importance of this cytokine in the early stages of infection, aswell as in the secondary adaptive response. Furthermore, the dualfunctions of IL-2 in both protective immunity and immune toleranceallows IL-2 to be a potential therapeutic in seemingly contrastingtherapies, as both an immune stimulant and an immune suppressor, forcancer and autoimmune disease, respectively.

The present disclosure in directed to IL-2Rβ ligands, IL-2Rγc ligands,and compounds comprising IL-2Rβ ligands and/or IL-2Rγc ligands.Compounds comprising IL-2Rβ ligands and IL-2Rγc ligands can be IL-2Ragonists including selective IL-2R agonists.

IL-2Rβ ligands and IL-2Rγc ligands provided by the present disclosurecomprise peptide domains amenable to strategies to simultaneously maskperipheral bioactivity, target delivery to a tumor, selectively activatecytotoxic anti-tumor cells, and direct IL-2 receptor activation at tumorsites. IL-2Rβ ligands and IL-2Rγc ligands and compounds comprisingIL-2Rβ ligands and/or IL-2Rγc ligands provided by the present disclosurecan also be used to treat autoimmune diseases.

IL-2Rα ligands and compounds comprising IL-2Rα ligands are disclosed inU.S. Provisional Application No. 62/856,305 filed on Jun. 3, 2019, whichis incorporated by reference in its entirety.

The IL-2R agonists and compounds comprising IL-2Rβ ligands and/orIL-2Rγc ligands can be designed to selectively activate a specific formof the IL-2 receptor. The small peptide IL-2R ligands, having an aminoacid sequence that is unrelated to that of the natural cytokine, and canselectively bind to and activate the IL-2Rβ and/or IL-2Rγc subunits toproduce therapeutic IL-2 activity, while avoiding the effects that havelimited clinical success of IL-2-based compounds in cancer therapy.Because the IL-2R peptide ligands are small, i.e. from 5 to 30 aminoacids, with very low immunogenic potential, the small peptide IL-2Rligands can be incorporated into compounds to enhance therapeuticefficacy. For example, this allows the affinity of the IL-2R peptideligands for each of the three IL-2R subunits to be tuned to direct theresponsiveness of a particular immune cell population and therebyaffords flexibility to chemically target tumor sites.

Peptide ligands for the IL-2Rβ and IL-2Rγc subunits can be identifiedfrom highly complex peptide diversity libraries such as phage displaylibraries, optimized by peptide synthesis, and can be assembled intomonomers, homooligomers, heterodimers, or into other compounds and canbe designed to bring the IL-2R and IL-2Rγc binding subunits into acompetent signaling conformation.

Small agonists of IL-2R provided by the present disclosure can activatecells that do not express the IL-2Rα subunit with a similar potency ascells that do express the IL-2Rα subunit thereby avoiding preferentialactivation of cells expressing the IL-2Rα such as Tregs. These IL-2Ragonists are referred to as selective IL-2Rβγc agonists. Because theselective IL-2R agonists provided by the present disclosure can bechemically-synthesized, the IL-2R agonists can be modified using naturaland/or non-natural amino acids to independently tailor binding affinityto each receptor subunit to optimize potency and efficacy, and toimprove metabolic stability. The small agonists also allow suchmodifications to be made with a low likelihood of inducingimmunogenicity. Also, due to their chemical malleability, peptides canbe “caged” to construct a reversibly inactive prodrug usingtumor-specific environmental triggers such as proteases, or complexessensitive to low pH. For example, the pH-dependent binding properties ofpeptides can be optimized by use of non-natural amino acids havingside-chain ionizable groups with pKa's in the range of pH 5.0 to pH 8.0.As with proteins, pharmacokinetic-enhancing moieties, such as PEG, canbe appended to peptides, either as part of, or independent of, the“caging” strategy. Finally, sites on a peptide can be reserved forattaching a variety of tumor targeting moieties, such as tumor-specificantibodies. These features of IL-2Rβγc agonists can be exploited in thedesign of optimal therapeutic candidates based on the IL-2Rβγc agonistsprovided by the present disclosure.

Certain compounds provided by the present disclosure comprise ligandsthat selectively activate a specific form of the IL-2 receptor. Theseagonists can stimulate cytotoxic tumor-targeted cell populations withoutinducing immunosuppressive activity of Tregs at tumor sites. Thecellular selectivity of the agonists can enhance the efficacy of IL-2for anti-tumor therapy.

Peptides having a binding affinity to the IL-2Rβγc subunits can beidentified by random peptide diversity generating systems in conjunctionwith an affinity enrichment process, for example, using peptides onplasmids or peptides on phage systems. Synthetic peptide librarytechnologies such as DNA-encoded peptide libraries can also be used.

Using such systems, random peptides are generally designed to have adefined number of amino acid residues in length, such as from 6 to 20amino acids. To generate a collection of oligonucleotides encoding therandom peptides, the codon motif (NNK)_(x), where N is nucleotide A, C,G, or T (equimolar; depending on the methodology employed, othernucleotides can be employed), K is G or T (equimolar), and x is aninteger corresponding to the number of amino acids in the peptide, suchas from 6 to 20, can be used to specify any one of the 32 possiblecodons resulting from the NNX motif: 1 for each of 12 amino acids, 2 foreach of 5 amino acids, 3 for each of 3 amino acids, and only one of thethree stop codons. Thus, the NNK motif encodes all of the amino acids,encodes only one stop codon, and reduces codon bias.

In the systems employed, the random peptides can be presented either onthe surface of a phage particle, as part of a fusion protein comprisingeither the pIII or the pVIII coat protein of a phage fd derivative(peptides on phage) or as a fusion protein with the LacI peptide fusionprotein bound to a plasmid (peptides on plasmids). The phage orplasmids, including the DNA encoding the peptides, can be identified andisolated by an affinity enrichment process using immobilized IL-2Rand/or IL-2Rγc subunits. The affinity enrichment process, sometimesreferred to as “panning,” involves multiple rounds of incubating thephage or plasmids with the immobilized receptor, collecting the phage orplasmids that bind to the receptor (along with the accompanying DNA),and producing more of the phage or plasmids (along with the accompanyingLacI-peptide fusion protein) collected. The extracellular domain (ECD)of the IL-2R and/or IL-2Rγc subunits can be used during panning. Anengineered form of the IL-2Rβ and IL-2Rγc can be expressed in hostcells, such as CHO cells. Following receptor harvesting, the receptorcan be tested for binding to IL-2Rβ or IL-2Rγc specific phage clones.Peptides can also be identified by panning IL-2R subunits fused to an Fcdomain. The IL-2 receptor, as well as its extracellular domain, can beproduced in recombinant host cells.

After several rounds of affinity enrichment, the phage or plasmids andaccompanying peptides can be examined by ELISA to determine if thepeptides bind specifically to the IL-2Rβ and/or IL-2Rγc subunits. Theassay can be performed using methods similar to those described for theaffinity enrichment process, except that after removing unbound phage,the wells can be treated with an antibody such as a rabbit anti-phageantibody, then with alkaline phosphatase (AP)-conjugated goatanti-rabbit antibody. The amount of alkaline phosphatase in each wellcan be determined by standard methods.

By comparing test wells with control wells without the IL-2 receptor,one can determine whether the fusion proteins bind to the receptorspecifically. The phage pools found to bind to the IL-2R and/or IL-2Rγcsubunits can be screened in a colony lift probing format usingradiolabeled monovalent receptor. This probe can be produced usingprotein kinase A to phosphorylate a peptide sequence fused to theC-terminus of the soluble receptor. The receptor can then be labeled tohigh specific activity with ³³P for use as a monovalent probe toidentify high affinity ligands using colony lifts.

Peptides found to bind specifically to the IL-2Rβ subunits or IL-2Rγcsubunits can then synthesized as the free peptide (e.g., no phage) andtested in a blocking assay. The blocking assay can be carried out insimilar manner to the ELISA, except that IL-2Rβ or IL-2Rγc bindingpeptides or a reference peptide can be added to the wells before atracer compound for which receptor binding can be detected. Examples oftracer compounds include a specific phage clone bearing areceptor-binding peptide, a radiolabeled or biotinylated peptide knownto bind to the receptor, or a labeled variant of IL-2. Peptides thatblocked tracer binding to IL-2Rβ or IL-2Rγc are preferred compounds ofthe invention.

When using random peptide generation systems that allow for multivalentligand-receptor interaction, the density of the immobilized receptor canbe an important factor in determining the affinity of the ligands thatcan bind to the immobilized receptor. At higher receptor densities, suchas, when each anti-receptor antibody-coated well is treated with 0.25 mgto 0.5 mg of receptor, multivalent binding is more likely to occur thanat lower receptor densities (e.g., each anti-receptor antibody-coatedwell treated with 0.5 to 1 ng of the receptor). If multivalent bindingis occurring, then one will be more likely to isolate ligands withrelatively lower affinity, unless one uses high densities of immobilizedreceptor to identify lead compounds and uses lower receptor densities toisolate higher affinity derivative compounds.

Screening methods that can be used to identify peptides that bind IL-2Rcan involve first identifying lead peptides which bind to theextracellular domain of the receptor and then synthesizing otherpeptides which resemble the lead peptides. For example, using peptideson phage system, a random library can be screened to discover a phagethat presents a peptide that binds to the IL-2Rβ and/or IL-2Rγcsubunits. The phage DNAs can be sequenced to determine the sequences ofthe peptides displayed on the surface of the phages.

For example, clones capable of specific binding to IL-2R can beidentified from a random linear library. The sequences of these peptidescan serve as the basis for the construction of other peptide librariesdesigned to contain a high frequency of derivatives of the initiallyidentified peptides. These libraries can be synthesized so as to favorthe production of peptides that differ from the binding peptide in onlya few residues. This approach involves the synthesis of anoligonucleotide with the binding peptide coding sequence, except thatrather than using pure preparations of each of the four nucleosidetriphosphates in the synthesis, mixtures of the four nucleosidetriphosphates (i.e., 55% of the “correct” nucleotide, and 15% each ofthe other three nucleotides is one preferred mixture for this purposeand 70% of the “correct” nucleotide and 10% of each of the other threenucleotides is another preferred mixture for this purpose) can be usedso as to generate derivatives of the binding peptide coding sequence.

A variety of strategies can be used to derivatize the lead peptides bymaking “mutagenesis on a theme” libraries, based on a consensus sequenceand mutagenized at 70:10:10:10 frequency with 5 NNK codons on eachterminus (probing with radiolabeled monovalent receptor and with orwithout peptide elution).

The “peptides on plasmids” method can also be used for peptide screeningand mutagenesis studies. According to this approach, random peptides canbe fused at the C-terminus of LacI through expression from a plasmidvector carrying the fusion gene. Linkage of the LacI-peptide fusion toits encoding DNA occurs via the lacO sequences on the plasmid, forming astable peptide-LacI-plasmid complex that can be screened by affinitypurification (panning) on an immobilized receptor. The plasmids thusisolated can then be reintroduced into E. coli by electroporation toamplify the selected population for additional rounds of screening, orfor the examination of individual clones.

In addition, random peptide screening and mutagenesis studies can beperformed using a modified C-terminal Lac-I display system in whichdisplay valency can be reduced. The libraries can be screened, and theresulting DNA inserts can be cloned as a pool into a maltose bindingprotein (MBP) vector allowing their expression as a C-terminal fusionprotein. Crude cell lysates from randomly picked individual MBP fusionclones can then assayed for IL-2R binding in an ELISA format.

A variety of methods can be used to evaluate IC₅₀ binding affinityvalues. For example, a competitive binding ELISA assay, an IL-2 tracer,an IL-2Rβ ligand tracer, or an IL-2Rγc ligand tracer, can be used todetermine whether the peptides inhibit the binding of the tracer to theextracellular domain of the IL-2 receptor. The IC₅₀ value can bedetermined using the free peptide, which optionally can be C-terminallyamidated, or can be prepared as an ester or other carboxy amide. Torecreate the exact sequence displayed by a phage, the N-terminal andC-terminal amino acids of the synthetic peptides can be preceded by oneor two glycine residues. These glycines are not believed to be necessaryfor binding or activity.

In general, peptides and peptidomimetics having an IC₅₀ of greater thanabout 100 μM lack sufficient binding affinity (IC₅₀) to be useful inimaging, targeting, diagnostic, and therapeutic applications. Forimaging, targeting, and diagnostic purposes, the peptides andpeptidomimetics can have an IC₅₀, for example, of about 1 μM or lessand, for pharmaceutical purposes, the peptides and peptidomimetics canhave an IC₅₀, for example, less than 100 μM, or less than 100 nM.

Robust and quantitative bioassays can be used to characterize thebiological activity of a compound exhibiting IL-2Rβγc agonist activity.The assays can measure the activation of the IL-2 receptor, measure thedownstream functional consequences of IL-2R activation and/or measuretherapeutically-relevant outcomes and functions of the activated IL-2receptor. The assays can be used to measure the therapeutic activity andpotency of an IL-2R selective agonist and compounds comprising an IL-2Rβand/or IL-2Rγc ligand and can also be used to measure thepharmacodynamics of an IL-2 selective agonist in animals or in humans.

Activation of the IL-2Rβγc subunits can be determined using a suitableassay. An example is an assay that can measure the phosphorylation ofthe signal transduction protein STAT5, measured flow cytometry with anantibody specific for the phosphorylated protein (pSTAT5).Phosphorylation of STAT5 is an essential step in the IL-2 signaltransduction pathway. Therefore, measurement of phosphorylated STAT5(pSTAT5) in cells will be recognized as reflective of IL-2 activation inthese cells and will be predictive of other biological outcomes of IL-2treatment given appropriate exposure time and conditions.

Another assay for assessing functional activation is to use an assaythat measures IL-2-stimulated proliferation of cells. Cell proliferationcan be determined, for example, by measuring the incorporation oftritiated thymidine into a purified T-cell population, by measuring anincrease in cell numbers of a particular T-cell type in a mixedpopulation of cells using flow cytometry, or by measuring the celldivision-associated dilution of a vital fluorescent dye such ascarboxyfluorescein succinimidyl ester (CFSE) by flow cytometry.

An IL-2Rβ ligand provided by the present disclosure can exhibit abinding affinity (IC₅₀) to the human IL-2Rβ subunit of less than 100 M,less than 10 μM, less than 1 μM, less than 0.1 μM, or less than 0.01 μM.

An IL-2Rβ ligand can exhibit a binding affinity (IC₅₀) to the humanIL-2Rβ subunit from 1 μM to 100 M, from 10 μM to 10 M, from 100 μM to 1μM, from 0.001 μM to 1 μM, or from 0.01 μM to 1 μM.

An IL-2Rβ ligand provided by the present disclosure can exhibit abinding affinity (IC₅₀) to a mammalian IL-2Rβ subunit of less than 100M, less than 10 M, less than 1 μM, less than 0.1 μM, or less than 0.01μM.

An IL-2Rβ ligand can exhibit a binding affinity (IC₅₀) to a mammalianIL-2Rβ subunit from 1 μM to 100 M, from 10 μM to 10 μM, from 100 μM to 1μM, from 0.001 μM to 1 μM, or from 0.01 μM to 1 μM.

An IL-2Rβ ligand provided by the present disclosure can exhibit abinding affinity (IC₅₀) to each of the human IL-2Rβ subunit and to thehuman IL-2Rγc subunit of less than 100 μM, less than 10 M, less than 1μM, less than 0.1 μM, or less than 0.01 μM.

An IL-2Rβ ligand can exhibit a binding affinity (IC₅₀) to each of thehuman IL-2Rβ subunit and to the human IL-2Rγc subunit from 1 μM to 100μM, from 10 μM to 10 μM, from 100 μM to 1 μM, from, 0.001 μM to 1 μM, orfrom 0.01 μM to 1 μM.

An IL-2Rβ ligand can exhibit a binding affinity (IC₅₀) to the humanIL-2Rα (CD25) subunit of greater than 100 M, greater than 1 mM, greaterthan 10 mM, or greater than 100 mM.

An IL-2Rβ ligand can exhibit a binding affinity (IC₅₀) to the humanIL-2Rβ subunit that is at least 10 times greater than the bindingaffinity (IC₅₀) of the IL-2Rβ ligand to the human IL-2Rα subunit, atleast 50 times greater, at least 100 times greater, at least 500 timesgreater, or at least 1,000 times greater.

An IL-2Rβ ligand can comprise an amino acid sequence selected from SEQID NO: 1 to SEQ ID NO: 193, from SEQ ID NO: 578 to SEQ ID NO: 903, andSEQ ID NO: 1028 to SEQ ID NO: 1050, and from SEQ ID NOS 1052-1064 and1084.

An IL-2Rβ ligand can comprise an amino acid sequence selected from SEQID NO: 1 to SEQ ID NO: 193 from SEQ ID NO: 578 to SEQ ID NO: 903, andSEQ ID NO: 1028 to SEQ ID NO: 1050, and from SEQ ID NOS 1052-1064 and1084 can independently comprise one or more of the followingconservative substitutions: amino acids having a small hydrophobic sidechain comprising alanine (A), glycine (G), proline (P), serine (S) orthreonine (T), or tyrosine (Y); amino acids having a hydroxyl-containingside chain comprising serine (S), threonine (T); amino acids having anacidic side chain comprising aspartate (D) or glutamate (E); amino acidshaving a polar neutral side chain comprising histidine (H), asparagine(N), glutamine (Q), serine (S), threonine (T), or tyrosine (Y); aminoacids having a basic side chain comprising arginine (R), lysine (K), orhistidine (H); amino acids having a large hydrophobic side chaincomprising isoleucine (I), leucine (L), methionine (M), valine (V),phenylalanine (F), tyrosine (Y), or tryptophan (W); and amino acidshaving an aromatic side chain comprising phenylalanine (F), histidine(H), tryptophan (W), or tyrosine (Y).

An IL-2Rβ ligand can have the amino acid sequence of Formula (1) (SEQ IDNO: 1), the amino acid sequence of Formula (1a) (SEQ ID NO: 2), or theamino acid sequence of Formula (1b) (SEQ ID NO: 3):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—  (1)

—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—  (1a)

—X¹—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—X¹²—  (1b)

-   -   wherein, X¹ is selected from A, D, E, F, G, I, K, L, M, N, P, Q,        S, T, V, W, and Y; X² is selected from A, C, D, E, F, G, H, K,        L, N, P, R, S, T, W, and Y; X³ is selected from A, D, E, F, G,        H, M, N, Q, R, S, T, W, and Y; X⁴ is selected from A, D, E, F,        G, I, K, L, M, N, Q, R, S, T, V, and Y; X⁵ is selected from A,        G, I, Q, S, T, V, and W; X⁶ is selected from A, D, E, G, H, K,        L, M, N, P, Q, R, S, T, and V; X⁷ is selected from F, I, K, L,        Q, and V; X⁸ is selected from D, F, G, H, M, N, W, and Y; X⁹ is        selected from A, D, E, M, P, Q, S, T, V, and W; X¹⁰ is selected        from D, F, I, L, M, S, T, V, and Y; X¹¹ is selected from D, E,        F, H, I, L, M, Q, S, T, V, W, and Y; and X¹² is selected from F,        I, L, M, N, S, V, W, and Y.

In IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selected from F, I, L,M, and V.

In IL-2Rβ ligands of Formula (1)-(1b), X² can be selected from D, E, F,G, H, L, N, P, R, S, T, W, and Y.

In IL-2Rβ ligands of Formula (1)-(1b), X⁵ can be A.

In IL-2Rβ ligands of Formula (1)-(1b), X⁶ can be selected from D, E, andQ.

In IL-2Rβ ligands of Formula (1)-(1b), X⁷ can be selected from F, I, L,and V.

In IL-2Rβ ligands of Formula (1)-(1b), X³ can be G.

In IL-2Rβ ligands of Formula (1)-(1b), X⁹ can be selected from D, E, andQ.

In IL-2Rβ ligands of Formula (1)-(1b), X¹⁰ can be selected from F, I, L,M, V, and Y.

In IL-2Rβ ligands of Formula (1)-(1b), X¹¹ can be selected from D and E.

In IL-2Rβ ligands of Formula (1)-(1b), X¹² can be selected from F, I, L,M, and V.

In IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selected from F, I, L,M, and V; X² can be selected from D, E, F, G, H, L, N, P, R, S, T, W,and Y; X³ can be selected from A, D, E, F, G, H, M, N, Q, R, S, T, W,and Y; X⁴ can be selected from A, D, E, F, G, I, K, L, M, N, Q, R, S, T,V, and Y; X⁵ can be A; X⁶ can be selected from D, E, and Q; X⁷ can beselected from F, I, L, and V; X⁸ can be G; X⁹ can be selected from D, E,and Q; X¹⁰ can be selected from F, I, L, M, V, and Y; X¹¹ can beselected from D and E; and X¹² can be selected from F, I, L, M, and V.

An IL-2Rβ ligand can comprise the amino acid sequence of Formula (1)(SEQ ID NO: 1052), the amino acid sequence of Formula (1a) (SEQ ID NO:1053), or the amino acid sequence of Formula (1b) (SEQ ID NO: 1054):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—  (1)

—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—  (1a)

—X¹—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—X —  (1b)

-   -   wherein, X¹ can be selected from an amino acid X² can be        selected from an amino acid; X³ can be selected from an amino        acid; X⁴ can be selected from an amino acid; X⁵ can be selected        from an amino acid comprising a small hydrophobic side chain; X⁶        can be selected from an amino acid; X⁷ can be selected from an        amino acid comprising a large hydrophobic side chain; X⁸ can be        selected from an amino acid comprising a small hydrophobic side        chain; X⁹ can be selected from an amino acid comprising a        polar-neutral or an acidic side chain; X¹⁰ can be selected from        an amino acid comprising a large hydrophobic side chain; X¹¹ can        be selected from an amino acid; and X² can be selected from an        amino acid comprising a large hydrophobic side chain.

In IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selected from an aminoacid comprising a large hydrophobic side chain; X² can be selected froman amino acid; X³ can be selected from an amino acid; X⁴ can be selectedfrom an amino acid; X⁵ can be selected from an amino acid comprising asmall hydrophobic side chain; X⁶ can be selected from an amino acidcomprising a polar-neutral or an acidic side chain; X⁷ can be selectedfrom an amino acid comprising a large hydrophobic side chain; X⁸ can beselected from an amino acid comprising a small hydrophobic side chain;X⁹ can be selected from an amino acid comprising a polar-neutral or anacidic side chain; X¹⁰ can be selected from an amino acid comprising alarge hydrophobic side chain; X¹¹ can be selected from an amino acidcomprising a polar-neutral or an acidic side chain; and X² can beselected from an amino acid comprising a large hydrophobic side chain.

In IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selected from I, L, M,V, F, W, and Y; X² can be selected from an amino acid; X³ can beselected from an amino acid; X⁴ can be selected from an amino acid; X⁵can be selected from A, G, P, S, and T; X⁶ can be selected from H, N, Q,S, T, Y, D, and E; X⁷ can be selected from I, L, M, V, F, W, and Y; X⁸can be selected from A, G, P, S, and T; X⁹ can be selected from H, N, Q,S, T, Y, D, and E; X¹⁰ can be selected from I, L, M, V, F, W, and Y; X¹¹can be selected from H, N, Q, S, T, Y, D, and E; and X¹² can be selectedfrom I, L, M, V, F, W, and Y.

In IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selected from I, L, M,V, F, W, and Y; X² can be selected from an amino acid; X³ can beselected from an amino acid; X⁴ can be selected from an amino acid; X⁵can be A; X⁶ can be selected from H, N, Q, S, T, Y, D, and E; X⁷ can beselected from I, L, M, V, F, W, and Y; X⁸ can be G; X⁹ can be selectedfrom H, N, Q, S, T, Y, D, and E; X¹⁰ can be selected from I, L, M, V, F,W, and Y; X¹¹ can be selected from H, N, Q, S, T, Y, D, and E; and X¹²can be selected from I, L, M, V, F, W, and Y.

In IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selected from I, L, M,and V.

In IL-2Rβ ligands of Formula (1)-(1b), X² can be selected from D and E.

In IL-2Rβ ligands of Formula (1)-(1b), X⁶ can be selected from Q, E, andD.

In IL-2Rβ ligands of Formula (1)-(1b), X⁷ can be selected from V, L, andI.

In IL-2Rβ ligands of Formula (1)-(1b), X⁹ can be selected from E, D, andQ.

In IL-2Rβ ligands of Formula (1)-(1b), X¹⁰ can be selected from L, V, I,and Y.

In IL-2Rβ ligands of Formula (1)-(1b), X¹¹ can be selected from D and E.

In IL-2Rβ ligands of Formula (1)-(1b), X¹² can be selected from L, I,and F.

In IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selected from L, I, F,and V; X² can be selected from D and E; X⁶ can be selected from Q, E,and D; X⁷ can be selected from V, L, and I; X⁸ can be G; X⁹ can beselected from E, D, and Q; X¹⁰ can be selected from L, V, I, and Y; X¹¹can be selected from D and E; and X¹² can be selected from L, I, and F.

In IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selected from F, I, M,and Y; X² can be selected from E, D, and R; X³ can be selected from andamino acid; X⁴ can be selected from an amino acid; X⁵ can be A; X⁶ canbe selected from A, P, and Q; X⁷ can be selected from I and V; X⁸ can beG; X⁹ can be selected from E and Q; X¹⁰ can be selected from I, L, andV; X¹¹ can be selected from E, D, and Q; and X¹² can be selected from Iand L.

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 4 to SEQ ID NO: 163:

SEQ ID NO: 4 Q D C S S A S V G T I C Y L SEQ ID NO: 5Q E C G V W D L W P D C W I SEQ ID NO: 6 A F C D E A R V G E L C V MSEQ ID NO: 7 D D C S T A Q V G E L C V M SEQ ID NO: 8D T C A I A Q L Y D L C D L SEQ ID NO: 9 D Y C R N S N V G D V C Y LSEQ ID NO: 10 E D C R Y A E V G V L C Q M SEQ ID NO: 11F D C Q T A E L G D L C I V SEQ ID NO: 12 F F C Y L I G Q D E F C E FSEQ ID NO: 13 F P C Q I A M I G E Y C D W SEQ ID NO: 14F R C W E A P V G E I C E L SEQ ID NO: 15 F S C D Q A T L G Q I C V ISEQ ID NO: 16 G D C Y F S Q I G E L C M L SEQ ID NO: 17G P C Q Q A K L G E L C D L SEQ ID NO: 18 I D C A Q A T V G Q Y C T LSEQ ID NO: 19 I D C S D A A V G A L C T Q SEQ ID NO: 20I D C T R A S L G D I C V W SEQ ID NO: 21 I E C E R A Q I G E V C Q ISEQ ID NO: 22 I F C G D A Q L G E V C S L SEQ ID NO: 23I F C Q F A R L G Q T C Q L SEQ ID NO: 24 I P C S I A Q L F S L C D VSEQ ID NO: 25 I P C Y L A E L G Q V C S L SEQ ID NO: 26K N C E V A R L G D Y C E I SEQ ID NO: 27 L A C S Q A P L G T L C E ISEQ ID NO: 28 L D C G I A L Q G Q L C D Y SEQ ID NO: 29L D C S L S S L G D Y C Y M SEQ ID NO: 30 L G C F E A Q I G M I C D LSEQ ID NO: 31 L H C Y L A V L G Q L C D V SEQ ID NO: 32L L C Q V A S L G D Y C T I SEQ ID NO: 33 L P C D M A D L F T L C D YSEQ ID NO: 34 L S C G I A Q I G Q V C D M SEQ ID NO: 35L W C Q D A Q I G D V C W L SEQ ID NO: 36 M E C F L A A V G Q I C E LSEQ ID NO: 37 M F C Q T A E V G Q M C L L SEQ ID NO: 38M L C W E A P V G D V C T I SEQ ID NO: 39 N F C S G A G L G E L C V ISEQ ID NO: 40 N L C E Y S K V G E V C V F SEQ ID NO: 41N Y C Y Q A L L D T Y C I L SEQ ID NO: 42 P D C W Y A G L G Q I C E FSEQ ID NO: 43 P S C W M A Q V G D L C F I SEQ ID NO: 44P T C D T A A V G D L C E F SEQ ID NO: 45 Q D C F Q A P I G S L C Y LSEQ ID NO: 46 Q W C Y M T D V G D L C E L SEQ ID NO: 47S D C H L A Q V G E F C F L SEQ ID NO: 48 S D C Y L S Q V G S L C D FSEQ ID NO: 49 S P C S E A S L F Q L C D L SEQ ID NO: 50S W C Q V G D F W D V C T S SEQ ID NO: 51 T E C W L Q A L G E L C D FSEQ ID NO: 52 V A C S S V Q V G E L C D F SEQ ID NO: 53V E C M M S S L G D L C S F SEQ ID NO: 54 V N C W E A Q V G W L C D WSEQ ID NO: 55 V T C D K A T V G Q M C S I SEQ ID NO: 56W S C D V A S V G S Y C M L SEQ ID NO: 57 X D C S E A L L G Q I C T YSEQ ID NO: 58 Y D C R I A Q V G E L C D L SEQ ID NO: 59Y E C F Q A Q V G Q L C D V SEQ ID NO: 60 V D C S R A V V G E L C V NSEQ ID NO: 61 Q A C E V A K V G E L C D L SEQ ID NO: 62I R C E D A L L G D F C I F SEQ ID NO: 63 L F C H Q A Q I G E L C S VSEQ ID NO: 64 P D C S V A L L G E S C S V SEQ ID NO: 65T G C N L A Q I G D L C D L SEQ ID NO: 66 I G C S L A R L G E Y C V ISEQ ID NO: 67 L E C W Q A Q K G D L C D L SEQ ID NO: 68M D C S D A H V G Q I C S I SEQ ID NO: 69 A L C Q A A Q V G Q L C D LSEQ ID NO: 70 L W C G D A S L G Q L C W L SEQ ID NO: 71D H C S E A Q I G Q L D H L SEQ ID NO: 72 L D C F Y A T L G Q V C S LSEQ ID NO: 73 P D C S E A L L G Q I C T Y SEQ ID NO: 74T G C W Q A P V G S L C E L SEQ ID NO: 75 S G C E Y A T L G S L C D LSEQ ID NO: 76 S L C S L A P L G S L C D L SEQ ID NO: 77S L C S M V G L G Q L C D L SEQ ID NO: 78 I P C S V A R V G W L C D LSEQ ID NO: 79 D P C Y A A V L N S L C D I SEQ ID NO: 80D S C Q N A P L G S Y C V L SEQ ID NO: 81 L P C S L A K L H E L C D ISEQ ID NO: 82 L S C S D A Q L M Q L C E I SEQ ID NO: 83C C Y Q A M V G D L C D F C SEQ ID NO: 84 S S A S V G T I SEQ ID NO: 85G V W D L W P D SEQ ID NO: 86 D E A R V G E L SEQ ID NO: 87S T A Q V G E L SEQ ID NO: 88 A I A Q L Y D L SEQ ID NO: 89R N S N V G D V SEQ ID NO: 90 R Y A E V G V L SEQ ID NO: 91Q T A E L G D L SEQ ID NO: 92 Y L I G Q D E F SEQ ID NO: 93Q I A M I G E Y SEQ ID NO: 94 W E A P V G E I SEQ ID NO: 95D Q A T L G Q I SEQ ID NO: 96 Y F S Q I G E L SEQ ID NO: 97Q Q A K L G E L SEQ ID NO: 98 A Q A T V G Q Y SEQ ID NO: 99S D A A V G A L SEQ ID NO: 100 T R A S L G D I SEQ ID NO: 101E R A Q I G E V SEQ ID NO: 102 G D A Q L G E V SEQ ID NO: 103Q F A R L G Q T SEQ ID NO: 104 S I A Q L F S L SEQ ID NO: 105Y L A E L G Q V SEQ ID NO: 106 E V A R L G D Y SEQ ID NO: 107S Q A P L G T L SEQ ID NO: 108 G I A L Q G Q L SEQ ID NO: 109S L S S L G D Y SEQ ID NO: 110 F E A Q I G M I SEQ ID NO: 111Y L A V L G Q L SEQ ID NO: 112 Q V A S L G D Y SEQ ID NO: 113D M A D L F T L SEQ ID NO: 114 G I A Q I G Q V SEQ ID NO: 115Q D A Q I G D V SEQ ID NO: 116 F L A A V G Q I SEQ ID NO: 117Q T A E V G Q M SEQ ID NO: 118 W E A P V G D V SEQ ID NO: 119S G A G L G E L SEQ ID NO: 120 E Y S K V G E V SEQ ID NO: 121Y Q A L L D T Y SEQ ID NO: 122 W Y A G L G Q I SEQ ID NO: 123W M A Q V G D L SEQ ID NO: 124 D T A A V G D L SEQ ID NO: 125F Q A P I G S L SEQ ID NO: 126 Y M T D V G D L SEQ ID NO: 127H L A Q V G E F SEQ ID NO: 128 Y L S Q V G S L SEQ ID NO: 129S E A S L F Q L SEQ ID NO: 130 Q V G D F W D V SEQ ID NO: 131W L Q A L G E L SEQ ID NO: 132 S S V Q V G E L SEQ ID NO: 133M M S S L G D L SEQ ID NO: 134 W E A Q V G W L SEQ ID NO: 135D K A T V G Q M SEQ ID NO: 136 D V A S V G S Y SEQ ID NO: 137S E A L L G Q I SEQ ID NO: 138 R I A Q V G E L SEQ ID NO: 139F Q A Q V G Q L SEQ ID NO: 140 S R A V V G E L SEQ ID NO: 141E V A K V G E L SEQ ID NO: 142 E D A L L G D F SEQ ID NO: 143H Q A Q I G E L SEQ ID NO: 144 S V A L L G E S SEQ ID NO: 145N L A Q I G D L SEQ ID NO: 146 S L A R L G E Y SEQ ID NO: 147W Q A Q K G D L SEQ ID NO: 148 S D A H V G Q I SEQ ID NO: 149Q A A Q V G Q L SEQ ID NO: 150 G D A S L G Q L SEQ ID NO: 151S E A Q I G Q L SEQ ID NO: 152 F Y A T L G Q V SEQ ID NO: 153S E A L L G Q I SEQ ID NO: 154 W Q A P V G S L SEQ ID NO: 155E Y A T L G S L SEQ ID NO: 156 S L A P L G S L SEQ ID NO: 157S M V G L G Q L SEQ ID NO: 158 S V A R V G W L SEQ ID NO: 159Y A A V L N S L SEQ ID NO: 160 Q N A P L G S Y SEQ ID NO: 161S L A K L H E L SEQ ID NO: 162 S D A Q L M Q L SEQ ID NO: 163Y Q A M V G D L

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 1 to SEQ ID NO: 163 and SEQ ID NOS 1052-1057, whereinthe amino acid sequence can be terminated with amino acids -G-G- on theN-terminus, on the C-terminus, or on both the N- and C-termini.

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 1 to SEQ ID NO: 163 and SEQ ID NOS 1052-1057, whereineach amino acid independently comprises one or more of the followingconservative substitutions: amino acids having a small hydrophobic sidechain comprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rβ ligands of SEQ ID NO: 1 to SEQ ID NO: 163 and SEQ ID NOS1052-1057 exhibit an affinity to the IL-2Rβ subunit of less than 100 μM.

An IL-2Rβ ligand can comprise the amino acid sequence of Formula (2)(SEQ ID NO: 164), the amino acid sequence of Formula (2a) (SEQ ID NO:165), or the amino acid sequence of Formula (2b) (SEQ ID NO: 166):

—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—  (2)

—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—  (2a)

—X¹³—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—X²⁴—  (2b)

-   -   wherein, X¹³ can be selected from A, D, E, G, N, Q, R, and V;        X¹⁴ can be selected from E, F, I, L, M, and Q; X¹⁵ can be        selected from D, G, L, and N; X¹⁶ can be selected from L, P, V,        and Y; X¹⁷ can be selected from F, G, and M; X¹⁸ can be selected        from A, D, N, and Q; X¹⁹ can be selected from F, I, L, S, V, W,        and Y; X²⁰ can be selected from D and W; X²¹ can be selected        from P and Y; X²² can be selected from A, D, Q, and S; X²³ can        be selected from I, L, Q, W, and Y; and X²⁴ can be selected from        E, F, I, L, T, V, and W.

In IL-2Rβ ligands of Formula (2)-(2b), X¹⁶ can be V.

In IL-2Rβ ligands of Formula (2)-(2b), X¹⁷ can be G.

In IL-2Rβ ligands of Formula (2)-(2b), X²⁰ can be W.

In IL-2Rβ ligands of Formula (2)-(2b), X²¹ can be P.

In IL-2Rβ ligands of Formula (2)-(2b), X¹³ can be selected from E, N,and Q; X¹⁴ can be selected from I and M; X¹⁵ can be selected from D, L,and N; X¹⁶ can be V; X¹⁷ can be G; X¹⁸ can be selected from D and Q; X¹⁹can be selected from V, W, and Y; X²⁰ can be W; X²¹ can be P; X²² can beselected from D and S; X²³ can be selected from L and Q; and X²⁴ can beselected from I, L, and V.

An IL-2Rβ ligand can comprise an amino acids sequence selected from anyone of SEQ ID NO: 167 to SEQ ID NO: 182:

SEQ ID NO: 167 E I C N V G Q V W P D C L L SEQ ID NO: 168G Q C L P G D F W P A C Y E SEQ ID NO: 169 N M C L V G D Y W P S C Q ISEQ ID NO: 170 Q I C D V G Q W W P D C Q V SEQ ID NO: 171V L C D Y M N S D Y Q C I T SEQ ID NO: 172 A E C G V G A I W P S C L WSEQ ID NO: 173 R L C D L F A I W P D C L F SEQ ID NO: 174D F C L V G D L W P S C W L SEQ ID NO: 175 N V G Q V W P DSEQ ID NO: 176 L P G D F W P A SEQ ID NO: 177 L V G D Y W P SSEQ ID NO: 178 D V G Q W W P D SEQ ID NO: 179 D Y M N S D Y QSEQ ID NO: 180 G V G A I W P S SEQ ID NO: 181 D L F A I W P DSEQ ID NO: 182 L V G D L W P S

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 164 to SEQ ID NO: 182 and SEQ ID NOS 1058-1060,wherein the amino acid sequence can be terminated with amino acids -G-G-on the N-terminus, on the C-terminus, or on both the N- and C-termini.

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 164 to SEQ ID NO: 182 and SEQ ID NOS 1058-1060,wherein each amino acid independently comprises one or more of thefollowing conservative substitutions: amino acids having a smallhydrophobic side chain comprising alanine (A), glycine (G), proline (P),serine (S), or threonine (T); amino acids having a hydroxyl-containingside chain comprising serine (S), threonine (T), or tyrosine (Y); aminoacids having an acidic side chain comprising aspartate (D) or glutamate(E); amino acids having a polar-neutral side chain comprising histidine(H), asparagine (N), glutamine (Q), serine (S), threonine (T), ortyrosine (Y); amino acids having a basic side chain comprising arginine(R), lysine (K), or histidine (H); amino acids having a largehydrophobic side chain comprising isoleucine (I), leucine (L),methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rβ ligands of SEQ ID NO: 164 to SEQ ID NO: 182 and SEQ ID NOS1058-1060 exhibit an affinity to the IL-2Rβ subunit of less than 100 μM.

An IL-2Rβ ligand can comprise the amino acid sequence of Formula (2)(SEQ ID NO: 1058), the amino acid sequence of Formula (2a) (SEQ ID NO:1059), or the amino acid sequence of Formula (2b) (SEQ ID NO: 1060):

—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²¹—  (2)

—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—  (2a)

—X¹³—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—X²⁴—  (2b)

-   -   wherein, X³ can be selected from an amino acid; X¹⁴ can be        selected from an amino acid comprising a large hydrophobic side        chain; X¹⁵ can be selected from an amino acid; X¹⁶ can be        selected from an amino acid comprising a large hydrophobic side        chain; X¹⁷ can be selected from an amino acid comprising a small        hydrophobic side chain; X¹⁸ can be selected from an amino acid;        X¹⁹ can be selected from an amino acid; X²⁰ can be selected from        an amino acid comprising a large hydrophobic side chain; X²¹ can        be selected from an amino acid comprising a small hydrophobic        side chain; X²² can be selected from an amino acid; X²³ can be        selected from an amino acid; and X²⁴ can be selected from an        amino acid comprising a large hydrophobic side chain.

In IL-2Rβ ligands of Formula (2)-(2b), X¹³ can be selected from an aminoacid; X¹⁴ can be selected from an amino acid comprising a largehydrophobic side chain; X¹⁵ can be selected from an amino acid; X¹⁶ canbe selected from an amino acid comprising a large hydrophobic sidechain; X¹⁷ can be selected from an amino acid comprising a smallhydrophobic side chain; X¹⁸ can be selected from an amino acidcomprising a polar-neutral or an acidic side chain; X¹⁹ can be selectedfrom an amino acid comprising large hydrophobic or neutral side chain;X²⁰ can be selected from an amino acid comprising a large hydrophobicside chain; X²¹ can be selected from an amino acid comprising a smallhydrophobic side chain; X²² can be selected from an amino acid; X²³ canbe selected from an amino acid; and X²⁴ can be selected from an aminoacid comprising a large hydrophobic side chain.

In IL-2Rβ ligands of Formula (2)-(2b), X¹³ can be selected from an aminoacid; X¹⁴ can be selected from I, L, M, V, F, W, and Y; X¹⁵ can beselected from D, E, I, L, M, V, F, Y, and W; X¹⁶ can be selected from I,L, M, N, V, F, Y, and W; X¹⁷ can be selected from A, G, P, S, and T; X¹⁸can be selected from H, N, Q, S, T, Y, D, and E; X¹⁹ can be selectedfrom I, L, M, V, F, W, and Y; X²⁰ can be selected from I, L, M, N, V, F,Y, and W; X²¹ can be selected from A, G, P, S, and T; X²² can beselected from an amino acid; X²³ can be selected from an amino acid; andX²⁴ can be selected from I, L, M, V, F, W, and Y.

In IL-2Rβ ligands of Formula (2)-(2b), X¹⁴ can be selected from I and M.

In IL-2Rβ ligands of Formula (2)-(2b), X¹⁶ can be V.

In IL-2Rβ ligands of Formula (2)-(2b), X¹⁷ can be G.

In IL-2Rβ ligands of Formula (2)-(2b), X¹⁸ can be selected from D and Q.

In IL-2Rβ ligands of Formula (2)-(2b), X²⁰ can be W.

In IL-2Rβ ligands of Formula (2)-(2b), X²¹ can be P.

In IL-2Rβ ligands of Formula (2)-(2b), X²³ can be selected from F, I, L,and V.

In IL-2Rβ ligands of Formula (2)-(2b), X¹³ can be selected from an aminoacid; X¹⁴ can be selected from I and M; X¹⁵ can be selected from anamino acid; X¹⁶ can be V; X¹⁷ can be G; X¹⁸ can be selected from D andQ; X¹⁹ can be selected from I, L, M, V, F, W, and Y; X²⁰ can be W; X²¹can be P; X²² can be selected from an amino acid; X²³ can be selectedfrom an amino acid; and X²⁴ can be selected from F, I, L, and V.

An IL-2Rβ ligand can comprise the amino acid sequence of Formula (3)(SEQ ID NO: 183) or the amino acid sequence of Formula (3a) (SEQ ID NO:184):

—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—  (3)

—X²⁵—C—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—C—X³⁶—  (3a)

-   -   wherein, X²⁵ can be selected from an amino acid; X²⁶ can be        selected from an amino acid; X²⁷ can be selected from I and V;        X²⁸ can be G; X²⁹ can be selected from D, E, and N; X³⁰ can be        selected from F, L, and Y; X³¹ can be selected from F, I, and V;        X³² can be selected from D and Q; X³³ can be selected from an        amino acid; X³⁴ can be selected from an amino acid; X³⁵ can be        selected from an amino acid; and X³⁶ can be selected from an        amino acid.

In IL-2RP ligands of Formula (3)-(3a), X²⁵ can be selected from L, S, T,and Y; X²⁶ can be selected from H and Q; X²⁷ can be selected from I andV; X²⁸ can be G; X²⁹ can be selected from D, E, and N; X³⁰ can beselected from F, L, and Y; X³¹ can be selected from F, I, and V; X³² canbe selected from D and Q; X³³ can be selected from D, L, and W; X³⁴ canbe selected from G, L, and T; X³⁵ can be selected from D, I, and S; andX³⁶ can be selected from A and M.

An IL-2Rβ ligand can comprise the amino acid sequence of Formula (3)(SEQ ID NO: 1061) or the amino acid sequence of Formula (3a) (SEQ ID NO:1062):

—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—  (3)

—X²⁵—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—C—X³⁶—  (3a)

-   -   wherein, X²⁵ can be selected from an amino acid; X²⁶ can be        selected from an amino acid; X²⁷ can be selected from an amino        acid comprising a large hydrophobic side chain; X²⁸ can be        selected from an amino acid comprising a small hydrophobic side        chain; X²⁹ can be selected from an amino acid comprising an        acidic side chain or a polar neutral side chain; X³⁰ can be        selected from an amino acid; X³¹ can be selected from an amino        acid; X³² can be selected from an amino acid comprising a        polar-neutral side chain or an acidic side chain; X³³ can be        selected from an amino acid; X³⁴ can be selected from an amino        acid; X³⁵ can be selected from an amino acid; and X³⁶ can be        selected from an amino acid.

In IL-2Rβ ligands of Formula (3)-(3a), X²⁵ can be selected from an aminoacid; X²⁶ can be selected from an amino acid; X²⁷ can be selected froman amino acid comprising a large hydrophobic side chain; X²⁸ can beselected from an amino acid comprising a small hydrophobic side chain;X²⁹ can be selected from an amino acid comprising an acidic side chainor a polar neutral side chain; X³⁰ can be selected from an amino acidcomprising a large hydrophobic side chain; X³¹ can be selected from anamino acid comprising a large hydrophobic side chain; X³² can beselected from an amino acid comprising a polar-neutral side chain or anacidic side chain; X³³ can be selected from an amino acid; X³⁴ can beselected from an amino acid; X³⁵ can be selected from an amino acid; andX³⁶ can be selected from an amino acid.

An IL-2Rβ ligand can comprise the amino acid sequence of Formula (3)(SEQ ID NO: 1063) or the amino acid sequence of Formula (3a) (SEQ ID NO:1064):

—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—  (3)

—X²⁵—C—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—C—X³⁶—  (3a)

-   -   wherein, X²⁵ can be selected from an amino acid; X²⁶ can be        selected from an amino acid; X²⁷ can be selected from I, L, M,        V, F, Y, and W; X²⁸ can be selected from A, G, P, S, and T; X²⁹        can be selected from D, E, H, N, Q, S, T, and Y; X³⁰ can be        selected from I, L, M, V, F, Y, and W; X³¹ can be selected from        I, L, M, V, F, Y, and W; X³² can be selected from D, E, H, N, Q,        T, and Y; X³³ can be selected from an amino acid; X³⁴ can be        selected from an amino acid; X³⁵ can be selected from an amino        acid; and X³⁶ can be selected from an amino acid.

In IL-2Rβ ligands of Formula (3)-(3a), X²⁷ can be selected from V and I.

In IL-2Rβ ligands of Formula (3)-(3a), X²⁸ can be G.

In IL-2Rβ ligands of Formula (3)-(3a), X²⁹ can be selected from D and E.

In IL-2Rβ ligands of Formula (3)-(3a), X³⁰ can be selected from V, L, F,and Y.

In IL-2Rβ ligands of Formula (3)-(3a), X³¹ can be selected from I, V,and F.

In IL-2Rβ ligands of Formula (3)-(3a), X³² can be selected from Q and D.

In IL-2Rβ ligands of Formula (3)-(3a), X²⁵ can be selected from an aminoacid; X²⁶ can be selected from an amino acid; X²⁷ can be selected from Vand I; X²⁸ can be G; X²⁹ can be selected from D and E; X³⁰ can beselected from V, L, F, and Y; X³¹ can be selected from I, V, and F; X³²can be selected from Q and D; X³³ can be selected from an amino acid;X³⁴ can be selected from an amino acid; X³⁵ can be selected from anamino acid; and X³⁶ can be selected from an amino acid.

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 185 to SEQ ID NO: 193:

SEQ ID NO: 185 L C H V G D Y I Q D G I C M SEQ ID NO: 186S C Q I G E L V D L T D C A SEQ ID NO: 187 T C Q V G D F F D W L S C ASEQ ID NO: 188 Y A C A E N V I D W L C T SEQ ID NO: 189L C H V G D Y I Q D G I C M SEQ ID NO: 190 S C Q I G E L V D L T D C ASEQ ID NO: 191 T C Q V G D F F D W L S C A SEQ ID NO: 192Y A C A E N V I D W L C T SEQ ID NO: 193 C V L L E H S S V G D I I C

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 183 to SEQ ID NO: 193 and SEQ ID NOS 1061-1064,wherein the amino acid sequence can be terminated with amino acids -G-G-on the N-terminus, on the C-terminus, or on both the N- and C-termini.

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 183 to SEQ ID NO: 193 and SEQ ID NOS 1061-1064,wherein each amino acid independently comprises one or more of thefollowing conservative substitutions: amino acids having a smallhydrophobic side chain comprising alanine (A), glycine (G), proline (P),serine (S), or threonine (T); amino acids having a hydroxyl-containingside chain comprising serine (S), threonine (T), or tyrosine (Y); aminoacids having an acidic side chain comprising aspartate (D) or glutamate(E); amino acids having a polar-neutral side chain comprising histidine(H), asparagine (N), glutamine (Q), serine (S), threonine (T), ortyrosine (Y); amino acids having a basic side chain comprising arginine(R), lysine (K), or histidine (H); and amino acids having a largehydrophobic side chain comprising isoleucine (I), leucine (L),methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rβ ligands of SEQ ID NO: 183 to SEQ ID NO: 193 and SEQ ID NOS1061-1064 exhibit an affinity to the IL-2Rβ subunit of less than 100 μM.

An IL-2Rβ ligand can comprise the amino acid sequence of Formula (13)(SEQ ID NO: 1028):

—X²⁰¹—X²⁰²—X²⁰³—X²⁰⁴—X²⁰⁵—X⁰⁶²—X²⁰⁷—X²⁰⁸—X²⁰⁹—X²¹⁰—X²¹¹—X²¹²—  (13)

-   -   wherein, X²⁰¹ can be selected from an amino acid; X²⁰² can be        selected from an amino acid; X²⁰² can be selected from an amino        acid comprising an acidic side chain; X²⁰⁴ can be selected from        an amino acid comprising a large hydrophobic side chain; X²⁰⁵        can be selected from an amino acid comprising a small        hydrophobic side chain; X²⁰⁶ can be selected from an amino acid        comprising an acidic side chain; X²⁰⁷ can be selected from an        amino acid comprising a large hydrophobic side chain; X²⁰⁸ can        be selected from an amino acid; X²⁰⁹ can be selected from an        amino acid comprising an acidic side chain; X²¹⁰ can be selected        from an amino acid; X²¹¹ can be selected from an amino acid; and        X²¹² can be selected from an amino acid comprising a large        hydrophobic side chain.

In IL-2Rβ ligands of Formula (13), X²⁰¹ can be selected from an aminoacid; X²⁰² can be selected from an amino acid; X²⁰³ can be selected fromD and E; X²⁰⁴ can be selected from I, L, M, V, F, Y, and W; X²⁰⁵ can beselected from A, G, P, S, and T; X²⁰⁶ can be selected from D and E; X²⁰⁷can be selected from I, L, M, V, F, Y, and W; X²⁰⁸ can be selected froman amino acid; X²⁰⁹ can be selected from D and E; X²¹⁰ can be selectedfrom an amino acid; X²¹¹ can be selected from an amino acid; and X²¹²can be selected from I, L, M, V, F, Y, and W.

In IL-2Rβ ligands of Formula (13), X²⁰¹ can be selected from C, F, L, S,and W; X²⁰² can be selected from C, D, F, G, L, M, Q, S, V, W, and Y;X²⁰³ can be selected from A, C, D, E, L, M, N, S, W, and Y; X²⁰⁴ can beselected from A, D, I, M, V, and W; X²⁰⁵ can be selected from D, E, G,and I; X²⁰⁶ can be selected from C, D, G, H, L, Q, S, and T; X²⁰⁷ can beselected from C, D, I, L, V, W, and Y; X²⁰⁸ can be selected from C, D,L, V, and W; X²⁰⁹ can be selected from C, D, G, I, M, N, P, Q, and W;X²¹⁰ can be selected from D. F. L. M. P, S, T, and Y; X²¹¹ can beselected from C, F, L, V, and W; and X²¹² can be selected from L, N, S,T, and V.

In IL-2Rβ ligands of Formula (13), X²⁰¹ can be selected from C, F, L, S,and W.

In IL-2Rβ ligands of Formula (13), X²⁰² can be selected from C, D, F, G,L, M, Q, S, V, W, and Y.

In IL-2Rβ ligands of Formula (13), X²⁰³ can be selected from D and E.

In IL-2Rβ ligands of Formula (13), X²⁰⁴ can be V.

In IL-2Rβ ligands of Formula (13), X²⁰⁵ can be G.

In IL-2Rβ ligands of Formula (13), X²⁰⁶ can be D.

In IL-2Rβ ligands of Formula (13), X²⁰⁷ can be selected from I, W, andY.

In IL-2Rβ ligands of Formula (13), X²⁰⁸ can be selected from C, D, L, V,and W.

In IL-2Rβ ligands of Formula (13), X²⁰⁹ can be D.

In IL-2Rβ ligands of Formula (13), X²¹⁰ can be selected from D, F, L, M,P, S, T, and Y.

In IL-2Rβ ligands of Formula (13), X²¹¹ can be selected from C, F, L, V,and W.

In IL-2Rβ ligands of Formula (13), X²¹² can be selected from L and V.

In IL-2Rβ ligands of Formula (13), X²⁰¹ can be selected from an aminoacid; X²⁰² can be selected from an amino acid; X²⁰³ can be selected fromD and E; X²⁰⁴ can be V; X²⁰⁵ can be G; X²⁰⁶ can be D; X²⁰⁷ can beselected from I, Y, and W; X²⁰⁸ can be selected from an amino acid; X²⁰⁹can be D; X²¹⁰ can be selected from an amino acid; X²¹¹ can be selectedfrom an amino acid; and X²¹² can be selected from I, L, M, V, F, Y, andW.

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 1029 to SEQ ID NO: 1043 and SEQ ID NO: 1084:

SEQ ID NO: 1029 C Q S V G D W C D M SEQ ID NO: 1030C D A V G S W C D F C SEQ ID NO: 1031 C F T V G D Y C G YSEQ ID NO: 1032 W C S D I G Q Y C D Y SEQ ID NO: 1033C Y E V G D Y C Q S SEQ ID NO: 1034 C G M A I G D L C M SEQ ID NO: 1035C L E V G C I W D M F V SEQ ID NO: 1036 F C D M G T V W P D L SSEQ ID NO: 1037 D C M L Y E L C D I D V L SEQ ID NO: 1038S C C V G D I W D T F SEQ ID NO: 1039 R W G D V G D L L M P F LSEQ ID NO: 1040 F L V C D D H Y C W L W T SEQ ID NO: 1041W E S W N V G D L V N L V N W SEQ ID NO: 1042 C Y E V G D Y C Q S P LSEQ ID NO: 1043 R W G D V G D L L M P L

An IL-2β ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 1028 to SEQ ID NO: 1043 and SEQ ID NO: 1084, whereinthe amino acid sequence can be terminated with amino acids -G-G- on theN-terminus, on the C-terminus, or on both the N- and C-termini.

An IL-2β ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 1028 to SEQ ID NO: 1043 and SEQ ID NO: 1084, whereineach amino acid independently comprises one or more of the followingconservative substitutions: amino acids having a small hydrophobic sidechain comprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); and amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

An IL-203 ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 1044 to SEQ ID NO: 1050:

SEQ ID NO: 1044 R S C Y Y K R P R L W C S E SEQ ID NO: 1045I C Y Y S P S D N T T V C E SEQ ID NO: 1046A S C X W L V S F G R S V C L SEQ ID NO: 1047C L S I G F R D I C F Y R V SEQ ID NO: 1048 D C M L Y E L C D I D V LSEQ ID NO: 1049 F L V C D D H Y C W L W T SEQ ID NO: 1050I C Y Y S P S D N T T V C E

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 1044 to SEQ ID NO: 1050, wherein the amino acidsequence can be terminated with amino acids -G-G-on the N-terminus, onthe C-terminus, or on both the N- and C-termini.

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 1044 to SEQ ID NO: 1050, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); and amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rβ ligands of SEQ ID NO: 144 to SEQ ID NO: 150 exhibit an affinityto the IL-2Rβ subunit of less than 100 μM.

An IL-20 ligand can comprise the amino acid sequence of Formula (10)(SEQ ID NO: 578):

—X¹⁹¹—X¹⁹²—X¹⁹³—X¹⁹⁴—X¹⁹⁵—C—X¹⁹⁶—X¹⁹⁷—X¹⁹⁸—X¹⁹⁹—X²⁰⁰—X²⁰¹—X²⁰²—X²⁰³—X²⁰⁴—X²⁰⁵—X²⁰⁶—X²⁰⁷—X²⁰⁸—  (10)

-   -   wherein, X¹⁹¹ can be selected from an amino acid comprising a        large hydrophobic side chain or an aromatic side chain; X¹⁹² can        be selected from an amino acid; X¹⁹³ can be selected from an        amino acid comprising a large hydrophobic side chain or an        aromatic side chain; X¹⁹⁴ can be selected from an amino acid        comprising a large hydrophobic side chain or a basic side chain;        X¹⁹⁵ can be selected from an amino acid comprising an acidic        side chain or a small hydrophobic side chain; X¹⁹⁶ can be        selected from an amino acid comprising a large hydrophobic side        chain or a basic side chain; X¹⁹⁷ can be selected from an amino        acid comprising a large hydrophobic side chain; X¹⁹⁸ can be        selected from an amino acid comprising a small hydrophobic side        chain; X¹⁹⁹ can be selected from an amino acid comprising a        polar/neutral side chain or a basic side chain; X²⁰⁰ can be        selected from an amino acid comprising a large hydrophobic side        chain; X²⁰¹ can be selected from an amino acid comprising a        small hydrophobic side chain; X²⁰² can be selected from an amino        acid comprising an acidic side chain or a polar/neutral side        chain; X²⁰³ can be selected from an amino acid comprising a        large hydrophobic side chain; X²⁰⁴ can be selected from an amino        acid comprising an acidic side chain; X²⁰⁵ can be selected from        an amino acid comprising a large hydrophobic side chain; X²⁰⁶        can be selected from an amino acid comprising an acidic side        chain or an aromatic side chain; X²⁰⁷ can be selected from an        amino acid comprising an amino acid; and X²⁰⁸ can be selected        from an amino acid comprising an acidic side chain.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, H, I, L,M, V, W, and Y; X¹⁹² can be selected from an amino acid; X¹⁹³ can beselected from F, H, I, L, M, V, W, and Y; X¹⁹⁴ can be selected from F,I, L, M, V, W, Y, H, K, and R; X¹⁹⁵ can be selected from D, E, A, G, P,S, and T; X¹⁹⁶ can be selected from F, I, L, M, V, W, Y, H, K, and R;X¹⁹⁷ can be selected from F, I, L, M, V, W, and Y; X¹⁹⁸ can be selectedfrom A, G, P, S, and T; X¹⁹⁹ can be selected from H, N, Q, S, T, Y, H,K, and R; X²⁰⁰ can be selected from F, I, L, M, V, W, and Y; X²⁰¹ can beselected from A, G, P, S, and T; X²⁰² can be selected from D, E, H, N,Q, S, T, and Y; X²⁰³ can be selected from F, I, L, M, V, W, and Y; X²⁰⁴can be selected from D and E; X²⁰⁵ can be selected from F, I, L, M, V,W, and Y; X²⁰⁶ can be selected from D, E, F, H, I, L, M, V, W, and Y;X²⁰⁷ can be selected from an amino acid; and X²⁰⁸ can be selected from Dand E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, H, W,and Y.

In IL-2Rβ ligands of Formula (10), X¹⁹² can be W.

In IL-2Rβ ligands of Formula (10), X¹⁹³ can be selected from an aminoacid.

In IL-2Rβ ligands of Formula (10), X¹⁹³ can be selected from F, H, W,and Y.

In IL-2Rβ ligands of Formula (10), X¹⁹³ can be selected from F, W, andY.

In IL-2Rβ ligands of Formula (10), X¹⁹⁴ can be selected from H, L, andY.

In IL-2Rβ ligands of Formula (10), X¹⁹⁴ can be L.

In IL-2Rβ ligands of Formula (10), X¹⁹⁴ can be Y.

In IL-2Rβ ligands of Formula (10), X¹⁹⁵ can be selected from D and P.

In IL-2Rβ ligands of Formula (10), X¹⁹⁵ can be D.

In IL-2Rβ ligands of Formula (10), X¹⁹⁵ can be P.

In IL-2Rβ ligands of Formula (10), X¹⁹⁶ can be selected from H and W.

In IL-2Rβ ligands of Formula (10), X¹⁹⁶ can be H.

In IL-2Rβ ligands of Formula (10), X¹⁹⁶ can be W.

In IL-2Rβ ligands of Formula (10), X¹⁹⁷ can be M.

In IL-2Rβ ligands of Formula (10), X¹⁹⁸ can be A.

In IL-2Rβ ligands of Formula (10), X¹⁹⁹ can be selected from H, K, R,and Q.

In IL-2Rβ ligands of Formula (10), X¹⁹⁹ can be Q.

In IL-2Rβ ligands of Formula (10), X¹⁹⁹ can be selected from H, K, andR.

In IL-2Rβ ligands of Formula (10), X²⁰⁰ can be selected from L and V.

In IL-2Rβ ligands of Formula (10), X²⁰⁰ can be L.

In IL-2Rβ ligands of Formula (10), X²⁰¹ can be G.

In IL-2Rβ ligands of Formula (10), X²⁰² can be selected from D, E, andQ.

In IL-2Rβ ligands of Formula (10), X²⁰² can be E.

In IL-2Rβ ligands of Formula (10), X²⁰³ can be L.

In IL-2Rβ ligands of Formula (10), X²⁰⁴ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X²⁰⁴ can be D.

In IL-2Rβ ligands of Formula (10), X²⁰⁵ can be L.

In IL-2Rβ ligands of Formula (10), X²⁰⁶ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X²⁰⁷ can be selected from an aminoacid.

In IL-2Rβ ligands of Formula (10), X²⁰⁸ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X²⁰⁹ can be selected from F, H, W,and Y; X¹⁹² can be selected from an amino acid; X¹⁹³ can be selectedfrom F, H, W, and Y; X¹⁹⁴ can be selected from H, L, and Y; X¹⁹⁵ can beselected from D and P; X¹⁹⁶ can be selected from H, R, and W; X¹⁹⁷ canbe M; X¹⁹⁸ can be A; X¹⁹⁹ can be selected from H, K, R, and Q; X²⁰⁰ canbe selected from L and V; X²⁰¹ can be G; X²⁰² can be selected from D, E,and Q; X²⁰³ can be L; X²⁰⁴ can be selected from D and E; X²⁰⁵ can be L;X²⁰⁶ can be selected from D, E, H, F, W, and Y; X²⁰⁷ can be selectedfrom an amino acid; and X²⁰⁸ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, H, W,and Y; X¹⁹² can be selected from an amino acid; X¹⁹³ can be Y; X¹⁹⁴ canbe selected from H, L, and Y; X¹⁹⁵ can be D; X¹⁹⁶ can be W; X¹⁹⁷ can beM; X¹⁹⁸ can be A; X¹⁹⁹ can be Q; X²⁰⁰ can be selected from L and V; X²⁰¹can be G; X²⁰² can be selected from D, E, and Q; X²⁰³ can be L; X²⁰⁴ canbe selected from D and E; X²⁰⁵ can be L; X²⁰⁶ can be selected from D andE; X²⁰⁷ can be selected from an amino acid; and X²⁰⁸ can be selectedfrom D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, H, W,and Y; X¹⁹² can be selected from an amino acid; X¹⁹³ can be Y; X¹⁹⁴ canbe selected from H, L, and Y; X¹⁹⁵ can be D; X¹⁹⁶ can be H; X¹⁹⁷ can beM; X¹⁹⁸ can be A; X¹⁹⁹ can be Q; X²⁰⁰ can be selected from L and V; X²⁰¹can be G; X²⁰² can be selected from D, E, and Q; X²⁰³ can be L; X²⁰⁴ canbe selected from D and E; X²⁰⁵ can be L; X²⁰⁶ can be selected from D andE; X²⁰⁷ can be selected from an amino acid; and X²⁰⁸ can be selectedfrom D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, H, W,and Y; X¹⁹² can be selected from an amino acid; X¹⁹³ can be Y; X¹⁹⁴ canbe selected from H, L, and Y; X¹⁹⁵ can be D; X¹⁹⁶ can be R; X¹⁹⁷ can beM; X¹⁹⁸ can be A; X¹⁹⁹ can be Q; X²⁰⁰ can be selected from L and V; X²⁰¹can be G; X²⁰² can be selected from D, E, and Q; X²⁰³ can be L; X²⁰⁴ canbe selected from D and E; X²⁰⁵ can be L; X²⁰⁶ can be selected from D andE; X²⁰⁷ can be selected from an amino acid; and X²⁰⁸ can be selectedfrom D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, H, W,and Y; X¹⁹² can be selected from an amino acid; X¹⁹³ can be Y; X¹⁹⁴ canbe selected from H, L, and Y; X¹⁹⁵ can be P; X¹⁹⁶ can be W; X¹⁹⁷ can beM; X¹⁹⁸ can be A; X¹⁹⁹ can be Q; X²⁰⁰ can be selected from L and V; X²⁰¹can be G; X²⁰² can be selected from D, E, and Q; X²⁰³ can be L; X²⁰⁴ canbe selected from D and E; X²⁰⁵ can be L; X²⁰⁶ can be selected from D andE; X²⁰⁷ can be selected from an amino acid; and X²⁰⁸ can be selectedfrom D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, H, W,and Y; X¹⁹² can be selected from an amino acid; X¹⁹³ can be Y; X¹⁹⁴ canbe selected from H, L, and Y; X¹⁹⁵ can be D; X¹⁹⁶ can be W; X¹⁹⁷ can beM; X¹⁹⁸ can be A; X¹⁹⁹ can be selected from H, K, and R; X²⁰⁰ can beselected from L and V; X²⁰¹ can be G; X²⁰² can be selected from D, E,and Q; X²⁰³ can be L; X²⁰⁴ can be selected from D and E; X²⁰⁵ can be L;X²⁰⁶ can be selected from D and E; X²⁰⁷ can be selected from an aminoacid; and X²⁰⁸ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, H, W,and Y; X¹⁹² can be selected from an amino acid; X¹⁹³ can be Y; X¹⁹⁴ canbe selected from H, L, and Y; X¹⁹⁵ can be D; X¹⁹⁶ can be W; X¹⁹⁷ can beM; X¹⁹⁸ can be A; X¹⁹⁹ can be Q; X²⁰⁰ can be selected from L and V; X²⁰¹can be G; X²⁰² can be selected from D, E, and Q; X²⁰³ can be L; X²⁰⁴ canbe selected from D and E; X²⁰⁵ can be L; X²⁰⁶ can be selected from F, H,W, and Y; X²⁰⁷ can be selected from an amino acid; and X²⁰⁸ can beselected from D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from A, D, E, F,G, H, I, K, L, N, M, P, Q, R, S, T, V, W, and Y; X¹⁹² can be selectedfrom A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; X¹⁹³can be selected from A, C, D, F, G, H, I, L, M, N P, R, S, T, V, W, andY; X¹⁹⁴ can be selected from F, H, I, K, L, N, P, Q, R, S, T, V, W, andY; X¹⁹⁵ can be selected from A, D, E, F, G, H, K, L, M, N, P, Q, S, W,and Y; X¹⁹⁶ can be selected from A, E, F, G, H, Q, R, S, W, and Y; X¹⁹⁷can be selected from A, D, E, F, I, K, L, M, N, Q, R, S, T, V, W, and Y;X¹⁹⁸ can be A; X¹⁹⁹ can be selected from A, D, H, K, L, N, P, Q, R, S,and Y; X²⁰⁰ can be selected from I, L, M, P, and V; X²⁰¹ can be selectedfrom G, H, and W; X²⁰² can be selected from D, E, and Q; X²⁰³ can be L;X²⁰⁴ can be selected from A, D, E, H, I, L, T, V, and Y; X²⁰⁵ can beselected from F, I, L, M, V, W, and Y; X²⁰⁶ can be selected from A, D,E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; X²⁰⁷ can beselected from A, C, D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, W, andY; and X²⁰⁸ can be selected from A, D, E, F, G, H, K, L, M, N, P, Q, R,S, T, V, W, and Y.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, H, W,and Y; X¹⁹² can be selected from A, D, E, F, G, H, I, K, L, M, N, P, Q,R, S, T, V, W, and Y; X¹⁹³ can be selected from F, H, W, and Y; X¹⁹⁴ canbe selected from F, H, I, L, V W, and Y; X¹⁹⁵ can be selected from D, E,and P; X¹⁹⁶ can be selected from F, H, R, S, W, and Y; X¹⁹⁷ can beselected from F, I, L, M, and V; X¹⁹⁸ can be A; X¹⁹⁹ can be selectedfrom H, K, N, Q, and R; X²⁰⁰ can be selected from I, L, and V; X²⁰¹ canbe G; X²⁰² can be selected from D, E, and Q; X²⁰³ can be selected fromF, I, L, M, V, and Y; X²⁰⁴ can be selected from D and E; X²⁰⁵ can be L;X²⁰⁶ can be selected from D, E, N, and Q; X²⁰⁷ can be selected from A,D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, W, and Y; and X²⁰⁸ can beselected from D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be W; X¹⁹² can be selectedfrom A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; X¹⁹³can be selected from F, H, W, and Y; X¹⁹⁴ can be Y; X¹⁹⁵ can be selectedfrom D, E, and P; X¹⁹⁶ can be selected from H, R, and W; X¹⁹⁷ can beselected from I and M; X¹⁹⁸ can be A; X¹⁹⁹ can be selected from K, Q,and R; X²⁰⁰ can be selected from I, L, and V; X²⁰¹ can be G; X²⁰² can beE; X²⁰³ can be L; X²⁰⁴ can be D; X²⁰⁵ can be L; X²⁰⁶ can be selectedfrom D and E; X²⁰⁷ can be selected from A, D, E, F, G, H, I, L, M, N, P,Q, R, S, T, V, W, and Y; and X²⁰⁸ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from A, D, E, F,G, H, I, K, L, N, M, P, Q, R, S, T, V, W, and Y; X¹⁹² can be selectedfrom A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y; X¹⁹³can be selected from F, H, W, and Y; X¹⁹⁴ can be selected from F, H, L,W, and Y; X¹⁹⁵ can be selected from D, E, and P; X¹⁹⁶ can be selectedfrom F, H, R, S, W, and Y; X¹⁹⁷ can be selected from F, I, L, M, and V;X¹⁹⁸ can be A; X¹⁹⁹ can be selected from H, K, Q, N, and R; X²⁰⁰ can beselected from I, L, and V; X²⁰¹ can be G; X²⁰² can be selected from D,E, and Q; X²⁰³ can be L; X²⁰⁴ can be selected from D and E; X²⁰⁵ can beselected from F, I, L, M, V, and W; X²⁰⁶ can be selected from D, E, F,I, L, M, V, W, and Y; X²⁰⁷ can be selected from A, D, E, F, G, H, I, L,M, N, P, Q, R, S, T, V, W, and Y; and X²⁰⁸ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from A, D, E, F,G, H, I, K, L, N, M, P, Q, R, S, T, V, W, and Y.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from A, G, P, S,and T.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, H, I, L,M, V, W, and Y.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, H, W,and Y.

In IL-2Rβ ligands of Formula (10), X¹⁹² can be selected from A, D, E, F,G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rβ ligands of Formula (10), X¹⁹² can be selected from A, G, P, S,and T.

In IL-2Rβ ligands of Formula (10), X¹⁹² can be selected from F, H, I, L,M, V, W, and Y.

In IL-2Rβ ligands of Formula (10), X¹⁹³ can be selected from F, H, W,and Y.

In IL-2Rβ ligands of Formula (10), X¹⁹³ can be W.

In IL-2Rβ ligands of Formula (10), X¹⁹⁴ can be selected from F, H, L, W,and Y.

In IL-2Rβ ligands of Formula (10), X¹⁹⁴ can be selected from H, L, andY.

In IL-2Rβ ligands of Formula (10), X¹⁹⁴ can be Y.

In IL-2Rβ ligands of Formula (10), X¹⁹⁵ can be selected from D, E, andP.

In IL-2Rβ ligands of Formula (10), X¹⁹⁵ can be D.

In IL-2Rβ ligands of Formula (10), X¹⁹⁵ can be P.

In IL-2Rβ ligands of Formula (10), X¹⁹⁶ can be selected from F, H, R, S,W, and Y.

In IL-2Rβ ligands of Formula (10), X¹⁹⁶ can be selected from H, R, andW.

In IL-2Rβ ligands of Formula (10), X¹⁹⁶ can be W.

In IL-2Rβ ligands of Formula (10), X¹⁹⁷ can be selected from F, I, L, M,and V.

In IL-2Rβ ligands of Formula (10), X¹⁹⁷ can be selected from I and M.

In IL-2Rβ ligands of Formula (10), X¹⁹⁷ can be M.

In IL-2Rβ ligands of Formula (10), X¹⁹⁸ can be A.

In IL-2Rβ ligands of Formula (10), X¹⁹⁹ can be selected from H, K, Q, N,and R.

In IL-2Rβ ligands of Formula (10), X¹⁹⁹ can be selected from H, K, andR.

In IL-2Rβ ligands of Formula (10), X¹⁹⁹ can be Q.

In IL-2Rβ ligands of Formula (10), X²⁰⁰ can be selected from I, L, andV.

In IL-2Rβ ligands of Formula (10), X²⁰⁰ can be selected from L and V.

In IL-2Rβ ligands of Formula (10), X²⁰¹ can be G.

In IL-2Rβ ligands of Formula (10), X²⁰² can be selected from D, E, andQ.

In IL-2Rβ ligands of Formula (10), X²⁰² can be E.

In IL-2Rβ ligands of Formula (10), X²⁰³ can be L.

In IL-2Rβ ligands of Formula (10), X²⁰⁴ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X²⁰⁴ can be D.

In IL-2Rβ ligands of Formula (10), X²⁰⁵ can be selected from F, I, L, M,V, and W.

In IL-2Rβ ligands of Formula (10), X²⁰⁵ can be L.

In IL-2Rβ ligands of Formula (10), X²⁰⁶ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X²⁰⁶ can be D.

In IL-2Rβ ligands of Formula (10), X²⁰⁶ can be selected from F, I, L, M,V, W, and Y.

In IL-2Rβ ligands of Formula (10), X²⁰⁷ can be selected from A, D, E, F,G, H, I, L, M, N, P, Q, R, S, T, V, W, and Y.

In IL-2Rβ ligands of Formula (10), X²⁰⁷ can be selected from A, G, P, S,and T.

In IL-2Rβ ligands of Formula (10), X²⁰⁷ can be selected from F, I, L, M,V, W, and Y.

In IL-2Rβ ligands of Formula (10), X²⁰⁸ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, I, L, M,V, W, and Y; X¹⁹² can be selected from A, D, E, F, G, H, I, K, L, M, N,P, Q, R, S, T, V, W, and Y; X¹⁹³ can be selected from F, H, W, and Y;X¹⁹⁴ can be selected from H, L, and Y; X¹⁹⁵ can be selected from D andP; X¹⁹⁶ can be selected from H, R, and W; X¹⁹⁷ can be selected from Iand M; X¹⁹⁸ can be A; X¹⁹⁹ can be selected from H, K, Q, and R; X²⁰⁰ canbe selected from L and V; X²⁰¹ can be G; X²⁰² can be selected from D, E,and Q; X²⁰³ can be L; X²⁰⁴ can be selected from D and E; X²⁰⁵ can be L;X²⁰⁶ can be selected from D, E, F, I, L, M, V, W, and Y; X²⁰⁷ can beselected from A, D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, W, and Y;and X²⁰⁸ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, I, L, M,V, W, and Y; X¹⁹² can be selected from A, D, E, F, G, H, I, K, L, M, N,P, Q, R, S, T, V, W, and Y; X¹⁹³ can be W; X¹⁹⁴ can be Y; X¹⁹⁵ can beselected from D and P; X¹⁹⁶ can be W; X¹⁹⁷ can be M; X¹⁹⁸ can be A; X¹⁹⁹can be Q; X¹⁹⁹ can be selected from H, K, and R; X²⁰⁰ can be selectedfrom L and V; X²⁰¹ can be G; X²⁰² can be E; X²⁰³ can be L; X²⁰⁴ can beselected from D and E; X²⁰⁵ can be L; X²⁰⁶ can be D; X²⁰⁷ can beselected from A, D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, W, and Y;and X²⁰⁸ can be selected from D and E.

In IL-2Rβ ligands of Formula (10), X¹⁹¹ can be selected from F, I, L, M,V, W, and Y; X¹⁹³ can be W; X¹⁹⁴ can be Y; X¹⁹⁵ can be selected from Dand P; X¹⁹⁶ can be selected from H, R, and W; X¹⁹⁷ can be M; X¹⁹⁸ can beA; X¹⁹⁹ can be selected from H, K, Q, and R; X²⁰⁰ can be selected from Land V; X²⁰¹ can be G; X²⁰² can be E; X²⁰³ can be L; X²⁰⁴ can be D; X²⁰⁵can be L; X²⁰⁶ can be D; X²⁰⁷ can be selected from A, D, E, F, G, H, I,L, M, N, P, Q, R, S, T, V, W, and Y; and X²⁰⁸ can be selected from D andE.

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 579 to SEQ ID NO: 808:

SEQ ID NO: 579 I Y C G F A P L G E L C I L SEQ ID NO: 580L P C W I A Q V G E L C D L SEQ ID NO: 581 L P C H M A Q L G E L C D LSEQ ID NO: 582 H P C W M A K V G E L C D L SEQ ID NO: 583Y P C H M A N V G E L C D L SEQ ID NO: 584S G S N D V P H C S M A D L G D L C H L SEQ ID NO: 585W H Q W L R K D C R F A K L G E L C D L SEQ ID NO: 586G R G V E Y K E C W M A S L G E L C T L SEQ ID NO: 587G R A D Q V L P C W M A Q L G E L C E L SEQ ID NO: 588I N Q S V L W P C H L A A V G D L C D L SEQ ID NO: 589L V G W N H Y D C S V A R V G E L C D L SEQ ID NO: 590Y P C W M A Q I G E L C D L SEQ ID NO: 591 Y P C H I A L L G E L C D LSEQ ID NO: 592 L Y C W Q A Q L G Q L C D L SEQ ID NO: 593Y D C R F A Q L G E L C D L SEQ ID NO: 594 L M C W N A Q L G D L C D LSEQ ID NO: 595 T M A S N W Y D C H M A Q V G E L C D L SEQ ID NO: 596L E Y D W N Q A C S K A H L G E L C V L SEQ ID NO: 597R I L Y E Y P D C W M A Q L G E L C E L SEQ ID NO: 598A Q A R F W H D C S I A H V G E L C D L SEQ ID NO: 599T A A E Y W Y P C W M A Q V G E L C D L SEQ ID NO: 600G P S M T Y K A C W M A Q L G E L C E L SEQ ID NO: 601Y F C H I A K L G E L C D L SEQ ID NO: 602 L A C R F A K L G E L C D LSEQ ID NO: 603 L P C W M A Q L G D L C D L SEQ ID NO: 604L Y R P N Y S D C S M A Q L G E L C E M SEQ ID NO: 605K L G K G W H D C S V A Q V G E L C D L SEQ ID NO: 606D V F K N W Y D C R I A K L G E L C D L SEQ ID NO: 607E Y V L K W P D C S S A Q L G E L C E L SEQ ID NO: 608R A L R K F H D C S T A R L G E L C D L SEQ ID NO: 609Q V E G S Y Y D C R W A H L G E L C D L SEQ ID NO: 610Y P C R M A K L G E L C D L SEQ ID NO: 611 Y P C W L A H V G E L C D LSEQ ID NO: 612 Y P C W M A Q L G E L C D L SEQ ID NO: 613Y D C S I A Q L G E L C D L SEQ ID NO: 614 L Y C W A A Q L G E L C D LSEQ ID NO: 615 L A C W M A H L G D L C D L SEQ ID NO: 616S S Y D M D Q D C R W A Q L G Q L C A I SEQ ID NO: 617M E N K Y W Y D C S V A L V G E L C D L SEQ ID NO: 618K V K L S W Y D C S V A Q V G E L C D L SEQ ID NO: 619G F L L E W Y D C R I A Q V G E L C D L SEQ ID NO: 620Y D S R S Y L P C H M A Q L G D L C D L SEQ ID NO: 621E S M G L G Y P C W R A Q L G E L C D L SEQ ID NO: 622Y P C W M A L V G E L C D L SEQ ID NO: 623 Y D C R F A L L G E L C D LSEQ ID NO: 624 Y W C W M A Q L G E L C D L SEQ ID NO: 625K W C W L A H L G E L C D L SEQ ID NO: 626 L P C W L A K V G D L C D LSEQ ID NO: 627 D H L Q R W W P C R L A R L G E L C D L SEQ ID NO: 628K S G Q R Y Y D C S M A Q L G E L C D L SEQ ID NO: 629E L V K T W Y P C W K A H V G E L C D L SEQ ID NO: 630R S L F L W H D C S T A Q L G E L C D L SEQ ID NO: 631L P R S G W Y D C S I A H V G E L C D L SEQ ID NO: 632L S V N K W Y P C W I A D V G E L C D W SEQ ID NO: 633Y P C W I A Q V G E L C D L SEQ ID NO: 634 L K C W M A Q L G E L C D LSEQ ID NO: 635 L D C R F A Q V G D L C D I SEQ ID NO: 636L W C W M A Q L G E L C D L SEQ ID NO: 637 Y P C W V A K L G E L C D FSEQ ID NO: 638 W S S K V V K P C H I A R L G E L C E L SEQ ID NO: 639L D E T Y W Y D C H V A Q V G E L C D L SEQ ID NO: 640T S L D S Y Y D C G M A K V G E L C D L SEQ ID NO: 641E S G H Y I K H C S I A L L G E L C H L SEQ ID NO: 642R T Y D P G Q D C R L A Q L G E L C E L SEQ ID NO: 643L M C W L A Q L G E L C E L SEQ ID NO: 644 Y P C W I A K V G E L C D LSEQ ID NO: 645 Y W C W M A Q V G E L C D L SEQ ID NO: 646Y E C H L A K L G E L C D L SEQ ID NO: 647R G R W E W Y D C S I A Q V G E L C D V SEQ ID NO: 648R S F E N W Y D C R I A Q L G E L C D L SEQ ID NO: 649P S S R G Y K P C W S A Q V G E L C E L SEQ ID NO: 650V D V S G W K P C Y M A H L G E L C D L SEQ ID NO: 651V E T T A W Y P C E L A Q L G E L C D L SEQ ID NO: 652L H C H N A Q V G D L C D L SEQ ID NO: 653 L W C H M A N L G D L C D LSEQ ID NO: 654 Y P C H I A Q V G E L C D L SEQ ID NO: 655Y P C H V A Q L G E L C D L SEQ ID NO: 656 Y D C S M A Q L G E L C D LSEQ ID NO: 657 Q W C W M A R L G E L C D L SEQ ID NO: 658L M V W D R R D C S T A Q L G E L C D L SEQ ID NO: 659T R N E F V Y P C W L A Q V G E L C D L SEQ ID NO: 660A V R N V W Y D C S F A R L H E L C D V SEQ ID NO: 661E V N W L Y Y D C R F A H L G E L C D L SEQ ID NO: 662R K T W I W K D C S I A R V G E L C D L SEQ ID NO: 663Y D C R I A Q V G E L C D L SEQ ID NO: 664Y P C H M A Q L G E L C D L W S W G D I SEQ ID NO: 665F D C R F A Q V G D L C D L W S P E H I SEQ ID NO: 666L P C W L A N V G E L C D L P G K F E R SEQ ID NO: 667Y D C R N A H V G E L C D L I D V P W E SEQ ID NO: 668L K C W M A Q V G E L C D L G V D D G Q SEQ ID NO: 669Y E C W M A K L G E L C D M Y L E G E I SEQ ID NO: 670G D V Y F C W N A K L G E L C D L F E M SEQ ID NO: 671V Q Y K K C W M A Q L G D L C E L D P S SEQ ID NO: 672P L C Y S C Q M A R V G E L C D L G C D SEQ ID NO: 673I G Y H A C W M A Q L G D L C D L H D N SEQ ID NO: 674M S W Y D C W M A Q V G E L C D L H V L SEQ ID NO: 675Y L C R F A Q L G E L C D L H V H W E D SEQ ID NO: 676Y Y C G I A N V G E L C D L E M G G N I SEQ ID NO: 677Y H C R F A Q V G E L C D L E P Q I T W SEQ ID NO: 678L G C W L A H V G E L C D L M F P G D E SEQ ID NO: 679G W H H W C H M A Q V G E L C D L Q V T SEQ ID NO: 680E T V S D C R M A Q V G E L C E Y H S A SEQ ID NO: 681W S W Y D C R I A Q I G E L C D L I I M SEQ ID NO: 682W L F Y D C R W A Q V G E L C D L S G D SEQ ID NO: 683Y P C W I A Q I G E L C D M D P R A N M SEQ ID NO: 684Y D C R F A Q L G E L C D L Y E T D G R SEQ ID NO: 685Y W C R F A Q V G E L C D V Q M Y A S Q SEQ ID NO: 686L P C W M A Q V G Q L C Y L D T E R H S SEQ ID NO: 687Y A C Y I A K L G E L C D L E M T D H G SEQ ID NO: 688P E W Y D C S T A Q V G E L C D L F D D SEQ ID NO: 689S S Y Y S C S M A Q L G E L C D L K L S SEQ ID NO: 690D R F N P C H M A Q L G E L C D L A R D SEQ ID NO: 691W L Y P E C R F A Q V G Q L C E F R N Q SEQ ID NO: 692A G W H P C H L A Q V G E L C D L D A L SEQ ID NO: 693Y A C W L A K V G E L C D M D E D F T I SEQ ID NO: 694Y S C G I A K V G E L C D L V D Q E P D SEQ ID NO: 695H P C H M A R L G E L C D L H S G V Y D SEQ ID NO: 696L Y C G F A Q V G D L C D L D V E V T Y SEQ ID NO: 697L P C W K A Y V G E L C D L N M P R L D SEQ ID NO: 698A E V K P C H M A Q V G D L C D L T G G SEQ ID NO: 699T P H Y P C W M A H M G E L C D L E W K SEQ ID NO: 700P I Y Q P C H M A A L G E L C D L G T A SEQ ID NO: 701S K F Y D C R I A K L G E L C D L R S G SEQ ID NO: 702L D W H A C W E A Q V G E L C D L R R S SEQ ID NO: 703L W C H M A N V G E L C D I D W T N G S SEQ ID NO: 704L A C H V A Q L G E L C D L W P D G V N SEQ ID NO: 705K P C Y M A Q V G E L C D L P A E S L S SEQ ID NO: 706Y D C S I A Q L G E L C D V E P W E S M SEQ ID NO: 707Y W C R W A Q V G E L C D L E V E N K D SEQ ID NO: 708L H C Y D A Q V G E L C D L E N W L H Q SEQ ID NO: 709I K M S P C H L A Q V G E L C D L Q W E SEQ ID NO: 710R H F L D C R I A Q I G D L C D L I G F SEQ ID NO: 711P A Y Y D C S I A K V G E L C D L S M M SEQ ID NO: 712V R F H D C S I A L V G D L C D L H M Y SEQ ID NO: 713V T P Y Y C W N A K L G E L C D M M W N SEQ ID NO: 714E Y S L D C R I A Q L G Q L C D L M R W SEQ ID NO: 715Y D C R M A K V G E L C D L W W D T L Y SEQ ID NO: 716Y D C H M A K L G E L C D L M L G D V T SEQ ID NO: 717Y P C H L A H V G E L C D L E G G T E F SEQ ID NO: 718Y D C S I A R V G E L C D L L Q D W W P SEQ ID NO: 719L P C W L A Q V G E L C D L Q E E T G S SEQ ID NO: 720D G H Y E C W K A Q L G E L C D L A G A SEQ ID NO: 721S F V Q D C S L A Q L W D L C E I W T D SEQ ID NO: 722E P F Y H C S I A Q L G E L C D L V R A SEQ ID NO: 723W P W Q D C S T A Q L G D L C D L M S Y SEQ ID NO: 724G L T L P C W M A Q L G E L C D L N N A SEQ ID NO: 725N L H Y D C R I A Q V G E L C D L T Y E SEQ ID NO: 726Y H C F L A Q V G D L C D L W D S M T T SEQ ID NO: 727R W C H M A Q L G D L C E L Y I F D K H SEQ ID NO: 728L P C H L A Q V G E L C D L P S S M L T SEQ ID NO: 729W A W L D C H N A Q V G E L C D L L R D SEQ ID NO: 730T S F H D C R I A N V G E L C D L S I L SEQ ID NO: 731V S W Y P C H M A Q V G E L C D L G F S SEQ ID NO: 732G N F K Q C H M A A V G E L C E M E N E SEQ ID NO: 733A V W Y D C R I A Q V G E L C D L V H P SEQ ID NO: 734Y D C F F A H V G E L C D L M G N S G T SEQ ID NO: 735K A C H M A Q L G E L C D L Y Q G G I N SEQ ID NO: 736Y P C W L A L P G E L C D L M E S T V N SEQ ID NO: 737Y D C S L A Q L G E L C D L T G P S Y G SEQ ID NO: 738Y P C H V A Q V G E L C D L S P G L H G SEQ ID NO: 739H M F Y P C W R A Q V G E L C D L A N Y SEQ ID NO: 740S G W Y P C R I A R L G E L C D L W E G SEQ ID NO: 741Q V H Y D C S M A Q L G E L C D L Y D E SEQ ID NO: 742L W F Y D C R F A H V G E L C D L E Q T SEQ ID NO: 743V G R Q M R K A C H M A L L G E L C D L SEQ ID NO: 744H W C W M A R L G E L C D L SEQ ID NO: 745S V L L S Y P L C R F A Q L G E L C D L SEQ ID NO: 746Y F C W M A K L G E L C D L SEQ ID NO: 747L H I L K N Y P C Y L A Q V G E L C D L SEQ ID NO: 748H I M R T W Y D C S I A Q I G E L C D L SEQ ID NO: 749P E R G G W Y D C R F A K L G E L C D L SEQ ID NO: 750G G M A K Y N P C H I A K L G E L C D L SEQ ID NO: 751Y F C W M A Q L G E L C D L SEQ ID NO: 752I S G L G I Y P C W M A H L G E L C D L SEQ ID NO: 753G V T Y Q W Y D C S I A L V G E L C D I SEQ ID NO: 754Y P C H L A L L G E L C D L SEQ ID NO: 755R P W R Q W Y D C S I A R L G E L C D I SEQ ID NO: 756Y P C W M A Q V G E L C D L SEQ ID NO: 757 Y D C S I A K L G E L C D LSEQ ID NO: 758 V S V W K D C S I A Q L G E L C D L SEQ ID NO: 759N E Q M I P W P C H L A Q L G D L C D L SEQ ID NO: 760F P C W L A K L G D L C D L SEQ ID NO: 761 Y W C H I A Q L G E L C D LSEQ ID NO: 762 D S N A P W Y D C S K A L L G E L C D L SEQ ID NO: 763W S I A N F Y D C R F A H L G E L C D L SEQ ID NO: 764L P C H M A L L G Q L C D L SEQ ID NO: 765 L M C W F A Q L G D L C D LSEQ ID NO: 766 Y P C W I A K L G E L C D F SEQ ID NO: 767A Y R A M P Y Y C W M A Q L G E L C D L SEQ ID NO: 768G S S V E I K P C W M A Y L G E L C H L SEQ ID NO: 769Y P C W L A R V G E L C D L D S G D V H SEQ ID NO: 770Y D C S M A L L G E L C D L W M P A I K SEQ ID NO: 771Y P C W M A H V G E L C D L E G W F G V SEQ ID NO: 772G V F Y D C R I A Q L G E L C D L W A S SEQ ID NO: 773Y K F L P C W R A R V G E L C D L D T A SEQ ID NO: 774A N F Y D C R Y A Q L G E L C D L M N V SEQ ID NO: 775R R A S W C H L A Q V G E L C D L L W E SEQ ID NO: 776H P C H M A Q V G E L C D L N F P Y V E SEQ ID NO: 777T P C Y M A K L G E L C D L E E W A L E SEQ ID NO: 778L W C W M A Q V G E L C D L E E R S F M SEQ ID NO: 779Y P C H M A Q L G E L C D L W S W G D I SEQ ID NO: 780L P C W K A N L G E L C D L Y D M G H S SEQ ID NO: 781W A F Y D C F T A Q V G E L C D L S I G SEQ ID NO: 782K T W Y D C R F A Q L G E L C D L N M N SEQ ID NO: 783L P C W L A R L G E L C D L Q Y E Y N D SEQ ID NO: 784F S F Q H C H M A Q L G E L C D L G Y E SEQ ID NO: 785Y P C R I A K L G E L C D L S E W Q Q L SEQ ID NO: 786Y A C W F A Q V G E L C D L E E D M V T SEQ ID NO: 787G F S H F C W E A Q V G E L C D L I Y G SEQ ID NO: 788L Y C W M A Q L G E L C D L E H V D W N SEQ ID NO: 789L W C G I A Q L G E L C D L E L G I H D SEQ ID NO: 790L L C W M A Q L G E L C D L E G E V M K SEQ ID NO: 791K V W Y P C R I A Q V G E L C D L D Q F SEQ ID NO: 792G E W Y D C R I A Q V G E L C D L W P V SEQ ID NO: 793Y P C W F A K L G E L C D L G L T D T K SEQ ID NO: 794V S W V D C H M A Q V G E L C D L R D S SEQ ID NO: 795Q F W L G C W M A Q V G E L C D L D Q P SEQ ID NO: 796Y T W L D C S V A Q L G Q L C D L W S M SEQ ID NO: 797A L S W L W Q D C A L A Q L G E L C D L SEQ ID NO: 798G D L V M F Y D C R F A R V G E L C D L SEQ ID NO: 799R L F D P D Q N C R F A L L G E L C L L SEQ ID NO: 800G S V W E F Y D C F I A R V G E L C D L SEQ ID NO: 801S D L M V W K P C W T A Q L G E L C D L SEQ ID NO: 802K Y C G F A Q L G E L C V L SEQ ID NO: 803Y P C W M A Q V G E L C D L F L E S V P SEQ ID NO: 804M G F Y P C W T A Q L G E L C D L S V D SEQ ID NO: 805P L N Y P C W I A Q L G E L C D L D L R SEQ ID NO: 806W K F Q D C R T A Q V G E L C D L W P Y SEQ ID NO: 807L Y C G M A H V G Q L C I L E D W R G A SEQ ID NO: 808W Y P C W M A Q L G E L C D L D

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 578 to SEQ ID NO: 808, wherein the amino acid sequencecan be terminated with amino acids -G-G- on the N-terminus, on theC-terminus, or on both the N- and C-termini.

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 578 to SEQ ID NO: 808, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); and amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rβ ligands of SEQ ID NO: 578 to SEQ ID NO: 808 exhibit an affinityto the IL-2Rβ subunit of less than 100 μM.

An IL-20 ligand can comprise the amino acid sequence of Formula (11)(SEQ ID NO: 809):

—X²¹¹—X²¹²—X²¹³—X²¹⁴—C—X²¹⁵—X²¹⁶—X²¹⁷—X²¹⁸—X²¹⁹—X²²⁰—X²²¹—X²²²—C—X²²³—X²²⁴—X²²⁵—  (11)

-   -   wherein, X²¹¹ can be selected from an amino acid; X²¹² can be        selected from an amino acid comprising an aromatic side chain;        X²¹³ can be selected from an amino acid comprising a large        hydrophobic side chain or an aromatic side chain; X²¹⁴ can be P;        X²¹⁵ can be selected from an amino acid comprising an aromatic        side chain; X²¹⁶ can be selected from an amino acid comprising a        large hydrophobic side chain; X²¹⁷ can be A; X²¹⁸ can be        selected from an amino acid comprising a basic side chain or a        polar/neutral side chain; X²¹⁹ can be selected from an amino        acid comprising a large hydrophobic side chain; X²²⁰ can be G;        X²²¹ can be selected from an amino acid comprising an acidic        side chain or a polar/neutral side chain; X²²² can be L; X²²³        can be D; X²²⁴ can be selected from an amino acid comprising a        large hydrophobic side chain; and X²²⁵ can be selected from an        amino acid comprising an acidic side chain.

In IL-2Rβ ligands of Formula (11), X²¹¹ can be selected from an aminoacid; X²¹² can be selected from F, H, W, and Y; X²¹³ can be selectedfrom F, H, I, L, M, V, W, and Y; X²¹⁴ can be P; X²¹⁵ can be selectedfrom F, H, W, and Y; X²¹⁶ can be selected from F, I, L, M, V, W, and Y;X²¹⁷ can be A; X²¹⁸ can be selected from K, R, H, N, Q, S, T, and Y;X²¹⁹ can be selected from F, I, L, M, V, W, and Y; X²²⁰ can be G; X²²¹can be selected from D, E, H, N, Q, S, T, and Y; X²²² can be L; X²²³ canbe D; X²²⁴ can be selected from F, I, L, M, V, W, and Y; and X²²⁵ can beselected from D and E.

In IL-2Rβ ligands of Formula (11), X²¹¹ can be selected from an aminoacid.

In IL-2Rβ ligands of Formula (11), X²¹¹ can be selected from H, K, andR.

In IL-2Rβ ligands of Formula (11), X²¹¹ can be selected from H and R.

In IL-2Rβ ligands of Formula (11), X²¹² can be selected from F, H, W,and Y.

In IL-2Rβ ligands of Formula (11), X²¹² can be W.

In IL-2Rβ ligands of Formula (11), X²¹³ can be selected from F, H, I, L,M, V, W, and Y.

In IL-2Rβ ligands of Formula (11), X²¹³ can be L.

In IL-2Rβ ligands of Formula (11), X²¹³ can be Y.

In IL-2Rβ ligands of Formula (11), X²¹⁴ can be P.

In IL-2Rβ ligands of Formula (11), X²¹⁵ can be selected from F, H, W,and Y.

In IL-2Rβ ligands of Formula (11), X²¹⁵ can be W.

In IL-2Rβ ligands of Formula (11), X²¹⁶ can be selected from F, I, L, M,V, W, and Y.

In IL-2Rβ ligands of Formula (11), X²¹⁶ can be M.

In IL-2Rβ ligands of Formula (11), X²¹⁷ can be A.

In IL-2Rβ ligands of Formula (11), X²¹⁸ can be selected from K, R, H, N,Q, S, T, and Y.

In IL-2Rβ ligands of Formula (11), X²¹⁸ can be selected from K and R.

In IL-2Rβ ligands of Formula (11), X²¹⁸ can be Q.

In IL-2Rβ ligands of Formula (11), X²¹⁹ can be selected from F, I, L, M,V, W, and Y.

In IL-2Rβ ligands of Formula (11), X²¹⁹ can be L.

In IL-2Rβ ligands of Formula (11), X²²⁰ can be G.

In IL-2Rβ ligands of Formula (11), X²²¹ can be selected from D, E, H, N,Q, S, T, and Y.

In IL-2Rβ ligands of Formula (11), X²²¹ can be E.

In IL-2Rβ ligands of Formula (11), X²²² can be L.

In IL-2Rβ ligands of Formula (11), X²²³ can be D.

In IL-2Rβ ligands of Formula (11), X²²⁴ can be selected from F, I, L, M,V, W, and Y.

In IL-2Rβ ligands of Formula (11), X²²⁴ can be L.

In IL-2Rβ ligands of Formula (11), X²²⁵ can be selected from D and E.

In IL-2Rβ ligands of Formula (11), X²¹¹ can be selected from H, K, andR; X²¹² can be W; X²¹³ can be Y; X²¹⁴ can be P; X²¹⁵ can be W; X²¹⁶ canbe M; X²¹⁷ can be A; X²¹⁸ can be selected N and Q; X²¹⁹ can be selectedfrom L and V; X²²⁰ can be G; X²²¹ can be selected from E, D, and Q; X²²²can be L; X²²³ can be D; X²²⁴ can be selected from L and M; and X²²⁵ canbe selected from D and E.

In IL-2Rβ ligands of Formula (11), X²¹¹ can be selected from A, D, E, G,H, L, M, N, Q, R, S, T, and V; X²¹² can be selected from C, F, W, and Y;X²¹³ can be selected from F, H, K, L, N, Q, R, S, W, and Y; X²¹⁴ can beP; X²¹⁵ can be selected from W and Y; X²¹⁶ can be selected from F, I, K,L, M, R, S, T, and V; X²¹⁷ can be A; X²¹⁸ can be selected from D, E, G,H, K, L, N, Q, R, S, and Y; X²¹⁹ can be selected from L, P, and V; X²²⁰can be selected from G, H, and W; X²²¹ can be selected from D, E, and Q;X²²² can be selected from L and M; X²²³ can be D; X²²⁴ can be selectedfrom L, M, Q, and V; and X²²⁵ can be selected from A, D, E, F, G, H, L,N, Q, T, and V.

In IL-2Rβ ligands of Formula (11), X²¹¹ can be selected from H an R;X²¹² can be selected from F and W; X²¹³ can be selected from F, L, W,and Y; X²¹⁴ can be P; X²¹⁵ can be selected from W and Y; X²¹⁶ can beselected from F, I, L, M, and V; X²¹⁷ can be A; X²¹⁸ can be selected D,E, H, K, N, Q, and R; X²¹⁹ can be selected from L and V; X²²⁰ can be G;X²²¹ can be selected from D, E, and Q; X²²² can be selected from L andM; X²²³ can be D; X²²⁴ can be selected L, M, and V; and X²²⁵ can beselected from D and E.

In IL-2Rβ ligands of Formula (11), X²¹¹ can be selected from H and R;X²¹² can be W; X²¹³ can be Y; X²¹⁴ can be P; X²¹⁵ can be W; X²¹⁶ can beM; X²¹⁷ can be A; X²¹⁸ can be Q; X²¹⁹ can be L; X²²⁰ can be G; X²²¹ canbe Q; X²²² can be L; X²²³ can be D; X²²⁴ can be L; and X²²⁵ can beselected from D and E.

In IL-2Rβ ligands of Formula (11), X²¹¹ can be selected from H and R;X²¹² can be W; X²¹³ can be L; X²¹⁴ can be P; X²¹⁵ can be W; X²¹⁶ can beM; X²¹⁷ can be A; X²¹⁸ can be Q; X²¹⁹ can be L; X²²⁰ can be G; X²²¹ canbe Q; X²²² can be L; X²²³ can be D; X²²⁴ can be L; and X²²⁵ can beselected from D and E.

In IL-2Rβ ligands of Formula (11), X²¹¹ can be selected from H and R;X²¹² can be W; X²¹³ can be Y; X²¹⁴ can be P; X²¹⁵ can be W; X²¹⁶ can beM; X²¹⁷ can be A; X²¹⁸ can be selected from K and R; X²¹⁹ can be L; X²²⁰can be G; X²²¹ can be Q; X²²² can be L; X²²³ can be D; X²²⁴ can be L;and X²²⁵ can be selected from D and E.

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 810 to SEQ ID NO: 903:

SEQ ID NO: 810 Q P C W L A Q V G D L C D L L W P G P L SEQ ID NO: 811W L P C W I A R L G D L C D L E SEQ ID NO: 812W Y P C W M A L L G E L C D Q E SEQ ID NO: 813W Y P C Y R A R L G E L C D L D SEQ ID NO: 814W Q R E W R W F P C W M A K L G D M C D L D SEQ ID NO: 815Q D E A V E W F P C W M A R L G E L C D L E SEQ ID NO: 816Y Y P C W M A R L G E L C D L D SEQ ID NO: 817S V V V N N W L P C W M A Q L G E L C D L D SEQ ID NO: 818W Y P C W L A Q L G D L C D L D SEQ ID NO: 819V M S P T R W L P C W I A K L G E L C D L E SEQ ID NO: 820W F P C W M A Q L G Q L C D L E SEQ ID NO: 821W R P C W R A Y L G E L C D L E A M P R A T SEQ ID NO: 822I R S C S P C W S A D V G E L C D L E C E W SEQ ID NO: 823S G H W Y P C W M A R L G E L C D M E E R A SEQ ID NO: 824W Y P C W M A Q L G E L C D L Q T M G Y S H SEQ ID NO: 825A G D W L P C W M A E L G E L C D L E G P T SEQ ID NO: 826W L P C W I A S L G E L C D L D T G K R Q G SEQ ID NO: 827W L P C W M A H L G Q L C D L D L P G K S M SEQ ID NO: 828E G V F F P C W I A R L G E L C D L D H G L SEQ ID NO: 829T G R W K P C W M A G L H E L C D L E G F R SEQ ID NO: 830R K H F Y P C W M A Q L G E L C D L E G M P SEQ ID NO: 831D I G Y Y P C W M A Q V G D L C D L D D SEQ ID NO: 832D S D W W P C W M A Q L G E L C D L E D SEQ ID NO: 833G E R W K P C W I A Q L G E L C D L D F N W SEQ ID NO: 834W W P C W M A Q L G E M C D L E Y P Y V P G SEQ ID NO: 835Q T K L E G W Y P C W M A Q L G E L C D L D SEQ ID NO: 836W G R K E Q W L P C W K A Q L G E L C D L E SEQ ID NO: 837V P R A N A W H P C W M A Q L G E L C D L E SEQ ID NO: 838G R Q Q K G W Y P C W L A Q L G E L C D M E SEQ ID NO: 839W L N R H L F N P C W M A R L G E L C D L E SEQ ID NO: 840A Q V R R E W Y P C W M A Q L G E L C D L T SEQ ID NO: 841E T E Q M S W Y P C W V A Q L W E L C D L D SEQ ID NO: 842W L P C W L A K L G E L C D L E W L P C W SEQ ID NO: 843E R R P D T W F P C W R A L V G E L C D L E SEQ ID NO: 844W G R N R S W Y P C W M A Q L G E L C D L E SEQ ID NO: 845Q D R R S P W Y P C W M A K L G E L C D L A SEQ ID NO: 846T R R W Y P C Y L A K L G E L C D L F E G G T R SEQ ID NO: 847S E Q W W P C W I A R L G E L C D L D R E L S E SEQ ID NO: 848W Y P C W V A Q L G E I C D L E M T G P D S W Y P SEQ ID NO: 849Q D G W L P C W M A Q L G E L C D L E Y K R SEQ ID NO: 850N R R W Y P C W M A Q L G E L C D L D S R P SEQ ID NO: 851F Y P C W M A H L G E L C D L D G D T D S M SEQ ID NO: 852K S N F F P C W I A Q L G Q L C D L E P E T SEQ ID NO: 853F Y P C W M A N L G E L C D L D F L R E L N SEQ ID NO: 854H A S W L P C W L A Q L G E L C D L E P N P SEQ ID NO: 855N G A W Y P C W M A Q V G E L C D L E E R W SEQ ID NO: 856W R R W Y P C W V A Q V G E L C D L E I E A SEQ ID NO: 857R Q A W Y P C W M A Q L G E L C D L E A E L SEQ ID NO: 858R Q R W Y P C W M A R L G E L C D L D E P T SEQ ID NO: 859N N S R E G W F P C W L A K L G D L C D L D SEQ ID NO: 860Y Y P C W M A Q L G E L C D L E SEQ ID NO: 861W Y P C W L A Q L G E L C D L D SEQ ID NO: 862S W H A E T W Y P C W L A Q V G E L C D L D SEQ ID NO: 863K M H K A V W L P C W M A Q V G E L C D L E SEQ ID NO: 864D V L G D R W Y P C W I A K L G E L C D L D SEQ ID NO: 865W Y P C W M A Q L G E L C D L D SEQ ID NO: 866K L Q S W R W Y P C W M A Q L G E L C D L D SEQ ID NO: 867N E P E G G F Y P C W L A Q L G E L C D L H SEQ ID NO: 868W Y P C W M A R L G E L C D L E SEQ ID NO: 869F Y P C W T A L L G E L C D L E P G P P A M SEQ ID NO: 870W G T T W R W Y P C W M A Q L G E L C D L E SEQ ID NO: 871A K G W D T W K P C W L A N L G E L C D L E SEQ ID NO: 872R D E S A G Y Y P C W I A Q L G E L C D L E SEQ ID NO: 873W Y P C W I A K L G E L C D L E SEQ ID NO: 874W Y P C W I A Q L G E L C D L D SEQ ID NO: 875W Y P C W L A K L G E L C D L D SEQ ID NO: 876Q G P V R L W Y P C W M A Q L G E L C D SEQ ID NO: 877W Y P C W M A Q P G E L C D V D SEQ ID NO: 878W H P C W I A Q L G E L C D L E SEQ ID NO: 879W Y P C W I A Q L G E L C D L E SEQ ID NO: 880V R P M G V W Y P C W I A Q L G E L C D L V SEQ ID NO: 881V P R W Y P C W I A Q L G E L C D L D S D D SEQ ID NO: 882Y R G W L P C W R A K L G D L C D L G Q P M SEQ ID NO: 883G E A W Y P C W L A R L G E L C D M D P R V SEQ ID NO: 884W Y P C W M A Q L G E L C D L D E S T R L T SEQ ID NO: 885I G S W W P C W M A Q L G E L C D L E P E L SEQ ID NO: 886G T T W Y P C W L A Q L G E L C D L D V L E SEQ ID NO: 887W W P C W M A Q L G D L C D L E E T S G G T SEQ ID NO: 888W Y P C W M A Q L G E L C D L G P T E S N L SEQ ID NO: 889W Y P C W M A N L G E L C D L E Y P S W A Q SEQ ID NO: 890R G M C Y P C W F A R L G E L C D L E C D Q SEQ ID NO: 891W Y P C W M A Q L G E L C D L D A G A R H L SEQ ID NO: 892K S G W Y P C W M A K L G E L C D L E A Q P SEQ ID NO: 893G P R F Y P C W I A Q L G E L C D L E D M G SEQ ID NO: 894R V T W Y P C W M A Q L G E L C D L E E S V SEQ ID NO: 895W L P C W M A Q L G D L C D L E Q Y V P L P SEQ ID NO: 896Y L P C W M A H L G E L C D L D S P L K A R SEQ ID NO: 897W Y P C W M A Q L G E L C D L D D H W P A M SEQ ID NO: 898W Y P C W R A Q L G E L C D L D P P I A V E SEQ ID NO: 899W Y P C W M A N L G E L C D L E A E R S P V SEQ ID NO: 900R D Q Y Y P C W M A Q L G E L C D L D E V F SEQ ID NO: 901W Y P C W M A Q L G D L C D L E K P V T E R SEQ ID NO: 902W Y P C W I A R L G E L C D L E T S G G F P SEQ ID NO: 903S G H C Y P C W L A G L G E L C D L N C G

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 809 to SEQ ID NO: 903, wherein the amino acid sequencecan be terminated with amino acids -G-G- on the N-terminus, on theC-terminus, or on both the N- and C-termini.

An IL-2Rβ ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 809 to SEQ ID NO: 903, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); and amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rβ ligands of SEQ ID NO: 809 to SEQ ID NO: 903 can exhibit a bindingaffinity (IC₅₀) to the IL-2Rβ subunit of less than 100 μM.

An IL-2Rβ ligand can comprise, for example, from 5 to 50 amino acids,from 5 to 40 amino acids, from 5 to 30 amino acids, from 5 to 30 aminoacids, from 6 to 25 amino acids, or from 7 to 20 amino acids.

An IL-2Rβ ligand can exhibit a binding affinity (IC₅₀) to the humanIL-2Rβ subunit, to a mammalian IL-2Rβ subunit, or to both the humanIL-2Rβ subunit and a mammalian IL-2Rβ subunit from 1 pM to 100 M, from10 pM to 10 M, from 100 pM to 1 μM, from, 0.001 μM to 1 μM, or from 0.01μM to 1 μM.

An IL-2Rβ ligand provided by the present disclosure can exhibit, forexample, a binding affinity (IC₅₀) to the human IL-2Rβ subunit from 0.1μM to 50 μM.

An IL-2Rβ ligand can exhibit a binding affinity (IC₅₀) to the humanIL-2Rβ subunit, to a mammalian IL-2Rβ subunit, or to both the humanIL-2Rβ subunit and a mammalian IL-2Rβ subunit of less than 100 μM, lessthan 10 μM, less than 1 μM, less than 0.1 μM, or less than 0.01 μM.

An IL-2Rβ ligand can exhibit a binding affinity (IC₅₀) to each of thehuman IL-2Rβ subunit and to the human IL-2Rγc subunit of less than 100μM, less than 10 μM, less than 1 μM, less than 0.1 μM, or less than 0.01μM.

An IL-2Rβ ligand can exhibit a binding affinity (IC₅₀) to each of thehuman IL-2Rβ subunit and to the human IL-2Rγc subunit from 1 pM to 100μM, from 10 pM to 10 μM, from 100 pM to 1 μM, from, 0.001 μM to 1 μM, orfrom 0.01 μM to 1 μM.

An IL-2Rβ ligand provided by the present disclosure can exhibit abinding affinity (IC₅₀) to the human IL-2Rα (CD25) subunit of greaterthan 100 M, greater than 1 mM, greater than 10 mM, or greater than 100mM.

An IL-2Rβ ligand can exhibit a binding affinity (IC₅₀) to the humanIL-2Rβ subunit that can be at least 10 times greater, at least 50 timesgreater, at least 100 time greater, at least 500 times greater, or atleast 1,000 times greater than the binding affinity of the IL-2Rβ ligandto the human IL-2Rα subunit.

An IL-2Rγc ligand provided by the present disclosure can exhibit abinding affinity (IC₅) to the human IL-2Rγc subunit of less than 100 pM,less than 10 μM, less than 1 μM, less than 0.1 μM, or less than 0.01 μM.

An IL-2Rγc ligand provided by the present disclosure can exhibit abinding affinity (IC₅) to the human IL-2Rγc subunit from 1 pM to 100 μM,from 10 pM to 10 M, from 100 μM to 1 μM, from, 0.001 μM to 1 μM, or from0.01 μM to 1 μM.

An IL-2Rγc ligand provided by the present disclosure can exhibit abinding affinity (IC₅₀) to a mammalian IL-2Rγc subunit, for example, ofless than 100 pM, less than 10 M, less than 1 μM, less than 0.1 μM, orless than 0.01 μM.

An IL-2Rγc ligand provided by the present disclosure can exhibit abinding affinity (IC₅₀) to a mammalian IL-2Rγc subunit, for example,from 1 pM to 100 μM, from 10 pM to 10 μM, from 100 pM to 1 μM, from,0.001 μM to 1 μM, or from 0.01 μM to 1 μM.

An IL-2Rγc ligand provided by the present disclosure can comprise anamino acid sequence selected from any one of SEQ ID NO: 194 to SEQ IDNO: 267 and SEQ ID NO: 904 to SEQ ID NO: 1027 and SEQ ID NOS 1065-1082.

An IL-2Rγc ligand provided by the present disclosure can comprise anamino acid sequence of any one of SEQ ID NO: 194 to SEQ ID NO: 267 andSEQ ID NO: 904 to SEQ ID NO: 1027 and SEQ ID NOS 1065-1082 independentlycomprising one or more of the following conservative substitutions:amino acids having a small hydrophobic side chain comprising alanine (A)or glycine (G); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving a acidic and polar-neutral side chain comprising aspartic acid(I) or glutamic acid (E); asparagine (N) or glutamine (Q); amino acidshaving aromatic side chains comprise phenylalanine (F), tryptophan (W),tyrosine (Y), or histidine (H); amino acids having a basic side chaincomprising arginine (R), lysine (K), or histidine (H); amino acidshaving a large hydrophobic side chain comprising isoleucine (I), leucine(L), methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W) and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

An IL-2Rγc ligand can comprise the amino acid sequence of Formula (4)(SEQ ID NO: 194) or the amino acid sequence of Formula (4a) (SEQ ID NO:195):

—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—  (4)

—X⁵¹—X⁵²—C—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—C—X⁶¹—X⁶²—  (4a)

-   -   wherein, X⁵¹ can be selected from G, I, K, L, Q, R, T, Y, and V;        X⁵² can be selected from A, D, E, H, I, L, M, R, S, T, V, and W;        X⁵³ can be selected from D, E, F, N, Q, S, and T; X⁵⁴ can be        selected from A, D, E, G, I, M, N, Q, R, S, and T; X⁵⁵ can be        selected from D, E, F, Q, S, T, W, and Y X⁵⁶ can be selected        from D, E, F, G, L, M, N, Q, and Y; X⁵⁷ can be selected from E,        G, N, S and Q; X⁵⁸ can be selected from I, K, M, P, T, and V;        X⁵⁹ can be selected from I, L, M, S, T, and V; X⁶⁰ can be        selected from F, I, and L; X⁶¹ can be selected from F, T, and W;        and X⁶² can be selected from A, E, F, G, I, K, L, M, N, P, Q, S,        T, V, W, and Y.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵¹ can be selected from I,L, and V.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵² can be selected from Sand T.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵³ can be selected from D,E, N, and Q.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁴ can be selected from D,E, N, and Q.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁵ can be selected from F,W, and Y.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁶ can be selected from D,E, N, and Q.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁷ can be G.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁸ can be selected from Iand V.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁹ can be selected from I,L, M, and V.

In IL-2Rγc ligands of Formula (4) and (4a), X⁶⁰ can be selected from F,I, and L.

In IL-2Rγc ligands of Formula (4) and (4a), X⁶¹ can be W.

In IL-2Rγc ligands of Formula (4) and (4a), X⁶² can be selected from Nand Q.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵¹ can be selected from I,L, and V; X⁵² can be selected from S and T; X⁵³ can be selected from D,E, N, and Q; X⁵⁴ can be selected from D and N; X⁵⁵ can be selected fromF, W, and Y; X⁵⁶ can be selected from D, E, N, and Q; X⁵⁷ can be G; X⁵⁸can be selected from I and V; X⁵⁹ can be selected from I, L, M, and V;X⁶⁰ can be selected from F, I, and L; X⁶¹ can be W; and X⁶² can beselected from N and Q.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 196 to SEQ ID NO: 210 and SEQ ID NO: 904 to SEQ ID NO:913:

SEQ ID NO: 196 Q L C Q I W Q E V L L C W P SEQ ID NO: 197I E C N R D E C P M I C W A SEQ ID NO: 198 K V C E M W G G V L L C W NSEQ ID NO: 199 L E C N N S Y G V L L C W S SEQ ID NO: 200R I C Q D F Q G V I L C W L SEQ ID NO: 201 R R C Q D Y L G I L L C W ESEQ ID NO: 202 R T C T E W E N V V L C W V SEQ ID NO: 203T S C F N F D G V L L C W Q SEQ ID NO: 204 V S C E S W Q G T L F C W QSEQ ID NO: 205 V T C Q D W N G V L L C F P SEQ ID NO: 206G T C Q E Y N G V M I C W G SEQ ID NO: 207 I A C S Q E M G I L L C W VSEQ ID NO: 208 K W C Q D W F G V L L C T V SEQ ID NO: 209L T C Q N W Q G V S L C W N SEQ ID NO: 210 L V C D D T L G V T L C W WSEQ ID NO: 904 I H C N S Q M G I L I C W Y SEQ ID NO: 905I M C D S S S G V S I C W T SEQ ID NO: 906 I T C Q T F N G V P L C W KSEQ ID NO: 907 L E C D A S M S V M I C W F SEQ ID NO: 908R V C Q D W L G V K L C W N SEQ ID NO: 909 V S C D G S S G V L L C W MSEQ ID NO: 910 Y L C D E S M G V K L C W F SEQ ID NO: 911V T C Q T W N Q V L L C W S SEQ ID NO: 912 L D C D T S M G V P L C W FSEQ ID NO: 913 V M C E D W G G V P I C W I

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 194 to SEQ ID NO: 210 and SEQ ID NO: 904 to SEQ ID NO:913 and SEQ ID NOS 1065-1070, wherein the amino acid sequence can beterminated with amino acids -G-G- on the N-terminus, on the C-terminus,or on both the N- and C-termini.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 194 to SEQ ID NO: 210 and SEQ ID NO: 904 to SEQ ID NO:913 and SEQ ID NOS 1065-1070, wherein each amino acid independentlycomprises one or more of the following conservative substitutions: aminoacids having a small hydrophobic side chain comprising alanine (A),glycine (G), proline (P), serine (S), or threonine (T); amino acidshaving a hydroxyl-containing side chain comprising serine (S), threonine(T), or tyrosine (Y); amino acids having an acidic side chain comprisingaspartate (D) or glutamate (E); amino acids having a polar-neutral sidechain comprising histidine (H), asparagine (N), glutamine (Q), serine(S), threonine (T), or tyrosine (Y); amino acids having a basic sidechain comprising arginine (R), lysine (K), or histidine (H); amino acidshaving a large hydrophobic side chain comprising isoleucine (I), leucine(L), methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rγc ligands of SEQ ID NO: 194 to SEQ ID NO: 210 and SEQ ID NO: 904to SEQ ID NO: 913 and SEQ ID NOS 1065-1070 exhibit a binding affinity(IC₅₀) to the IL-2Rγc subunit of less than 100 μM.

An IL-2Rγc ligand can comprise the amino acid sequence of Formula (4)(SEQ ID NO: 1065) or the amino acid sequence of Formula (4a) (SEQ ID NO:1066):

—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—  (4)

—X⁵¹—X⁵²—C—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—C—X⁶¹—X⁶²—  (4a)

-   -   wherein, X⁵¹ can be selected from an amino acid; X⁵² can be        selected from an amino acid; X⁵³ can be selected from an amino        acid comprising a polar-neutral side chain or an acidic side        chain; X⁵⁴ can be selected from an amino acid comprising a        polar-neutral side chain or an acidic side chain; X⁵⁵ can be        selected from an amino acid; X⁵⁶ can be selected from an amino        acid; X⁵⁷ can be selected from an amino acid comprising a small        hydrophobic side chain; X⁵⁸ can be selected from an amino acid        comprising a large hydrophobic side chain; X⁵⁹ can be selected        from an amino acid comprising a large hydrophobic side chain;        X⁶⁰ can be selected from an amino acid comprising a large        hydrophobic side chain; X⁶¹ can be selected from an amino acid        comprising a large hydrophobic side chain; and X⁶² can be        selected from an amino acid.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵¹ can be selected from anamino acid comprising a large hydrophobic side chain and a basic sidechain; X⁵² can be selected from an amino acid comprising ahydroxyl-containing side chain and a large hydrophobic side chain; X⁵³can be selected from an amino acid comprising a polar-neutral side chainor an acidic side chain; X⁵⁴ can be selected from an amino acidcomprising a polar-neutral side chain or an acidic side chain; X⁵⁵ canbe selected from an amino acid comprising a large hydrophobic sidechain; X⁵⁶ can be selected from an amino acid comprising a polar-neutralside chain or an acidic side chain; X⁵⁷ can be selected from an aminoacid comprising a small hydrophobic side chain; X⁵⁸ can be selected froman amino acid comprising a large hydrophobic side chain; X⁵⁹ can beselected from an amino acid comprising a large hydrophobic side chain;X⁶⁰ can be selected from an amino acid comprising a large hydrophobicside chain; X⁶¹ can be selected from an amino acid comprising a largehydrophobic side chain; and X⁶² can be selected from an amino acidcomprising a polar-neutral side chain.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵¹ can be selected from R,K, H, F, I, L, M, V, Y, and W; X⁵² can be selected from S, T, F, I, L,M, V, Y, and W; X⁵³ can be selected from D, E, H, N, Q, S, T, and Y; X⁵⁴can be selected from D, E, H, N, Q, S, T, and Y; X⁵⁵ can be selectedfrom F, I, L, M, V, Y, and W; X⁵⁶ can be selected from D, E, H, N, Q, S,T, and Y; X⁵⁷ can be selected from A, G, P, S, and T; X⁵⁸ can beselected from F, I, L, M, V, Y, and W; X⁵⁹ can be selected from F, I, L,M, V, Y, and W; X⁶⁰ can be selected from F, I, L, M, V, Y, and W; X⁶¹can be selected from F, I, L, M, V, Y, and W; and X⁶² can be selectedfrom H, N, Q, S, T, and Y.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵¹ can be selected from I,L, and V.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵² can be selected from Sand T.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵³ can be selected from D,E, and Q.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁴ can be selected from D,E, and N.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁵ can be selected from F,Y, and W.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁶ can be selected from D,E, N, and Q.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁷ can be G.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁸ can be selected from Iand V.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵⁹ can be selected from I,L, M, and V.

In IL-2Rγc ligands of Formula (4) and (4a), X⁶⁰ can be selected from F,I, and L.

In IL-2Rγc ligands of Formula (4) and (4a), X⁶¹ can be W.

In IL-2Rγc ligands of Formula (4) and (4a), X⁶² can be selected from Nand Q.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵¹ can be selected from I,L, and V; X⁵² can be selected from S and T; X⁵³ can be selected from D,E, and Q; X⁵⁴ can be selected from D, E, and N; X⁵⁵ can be selected fromF, Y, and W; X⁵⁶ can be selected from D, E, N, and Q; X⁵⁷ can be G; X⁵⁸can be selected from I and V; X⁵⁹ can be selected from I, L, M, and V;X⁶⁰ can be selected from F, I, and L; X⁶¹ can be W; and X⁶² can beselected from N and Q.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵¹ can be selected from G,I, K, L, Q, R, and V; X⁵² can be selected from A, D, E, H, I, L, M, R,S, T, V, and W; X⁵³ can be selected from D, E, F, N, Q, S, and T; X⁵⁴can be selected from A, D, E, G, I, M, N, R, S, and T; X⁵⁵ can beselected from D, E, F, Q, S, T, W, and Y; X⁵⁶ can be selected from D, E,F, G, L, M, N, Q, S, and Y; X⁵⁷ can be selected from C, E, G, N, Q, andS; X⁵⁸ can be selected from I, P, T, and V; X⁵⁹ can be selected from I,K, L, M, P, S, T, and V; X⁶⁰ can be selected from F, I, and L; X⁶¹ canbe selected from F, T, and W; and X⁶² can be selected from A, E, F, G,I, K, L, M, N, P, Q, S, T, V, W, and Y.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵¹ can be selected from I,L, and V; X⁵² can be selected from S and T; X⁵³ can be selected from D,E, N, and Q; X⁵⁴ can be selected from D, E, N, S, and T; X⁵⁵ can beselected from F, S, T, W, and Y; X⁵⁶ can be selected from D, E, N, andQ; X⁵⁷ can be selected from G and N; X⁵⁸ can be selected from I and V;X⁵⁹ can be selected from I, L, M, and V; X⁶⁰ can be selected from F, I,and L; X⁶¹ can be W; and X⁶² can be selected from N and Q.

In IL-2Rγc ligands of Formula (4) and (4a), X⁵¹ can be selected from I,L, and V; X⁵² can be selected from S and T; X⁵³ can be Q; X⁵⁴ can beselected from D, E, N, S, and T; X⁵⁵ can be selected from S, T, and W;X⁵⁶ can be selected from D, E, N, and Q; X⁵⁷ can be G; X⁵⁸ can be V; X⁵⁹can be L; X⁶⁰ can be L; X⁶¹ can be W; and X⁶² can be selected from N andQ.

An IL-2Rγc ligand can comprise the amino acid sequence of Formula (5)(SEQ ID NO: 211) or Formula (5a) (SEQ ID NO: 212):

—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—  (5)

—X⁷¹—X⁷²—C—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—C—X⁸¹—X⁸²—  (5a)

-   -   wherein, X⁷¹ can be selected from F, G, I, L, P, Q, R, T, and V;        X⁷² can be selected from A, D, E, I, M, R, S, T, and V; X⁷³ can        be selected from D, E, F, M, N, Q, S T, V, W, and Y; X⁷⁴ can be        selected from D, E, F, G, I, L, M, P, R, S, T, and V; X⁷⁵ can be        selected from F, H, L, W, and Y; X⁷⁶ can be selected from D, E,        H, L, N, Q, S, and T; X⁷⁷ can be selected from G, T, Q, and E;        X⁷⁸ can be selected from I, L, M, Q, and V; X⁷⁹ can be selected        from D, E, N, Q, and R; X⁸⁰ can be selected from D, F, I, and L;        X⁸¹ can be selected from F, I, L, R, T, W, and Y; and X⁸² can be        selected from A, F, G, H, I, L, N, P, Q, S, T, and W.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷¹ can be selected from I,L, and V.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷² can be selected from A,D, E, I, M, and V.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷³ can be selected from E,Q, and N.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁴ can be selected from Dand E.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁵ can be selected from F,W, and Y.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁶ can be selected from D,E, L, N, and Q.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁷ can be G.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁸ can be selected from I,M, and V.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁹ can be selected from D,E, Q, and R.

In IL-2Rγc ligands of Formula (5) and (5a), X⁸⁰ can be selected from F,I, and L.

In IL-2Rγc ligands of Formula (5) and (5a), X⁸¹ can be W.

In IL-2Rγc ligands of Formula (5) and (5a), X⁸² can be selected from Nand Q.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷¹ can be selected from I,L, and V; X⁷² can be selected from A, D, E, I, M, and V; X⁷³ can beselected from E, Q, and N; X⁷⁴ can be selected from D and E; X⁷⁵ can beselected from F, W, and Y; X⁷⁶ can be selected from D, E, L, N, and Q;X⁷⁷ can be G; X⁷⁸ can be selected from I, M, and V; X⁷⁹ can be selectedfrom D, E, Q, and R; X⁸⁰ can be selected from F, I, and L; X⁸¹ can be W;and X⁸² can be selected from N and Q.

An IL-2Rγc ligand can comprise the amino acid sequence of Formula (5)(SEQ ID NO: 1071) or Formula (5a) (SEQ ID NO: 1072):

—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—  (5)

—X⁷¹—X⁷²—C—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—C—X⁸¹—X⁸²—  (5a)

-   -   wherein, X⁷¹ can be selected from an amino acid; X⁷² can be        selected from an amino acid; X⁷³ can be selected from an amino        acid; X⁷⁴ can be selected from an amino acid; X⁷⁵ can be        selected from an amino acid comprising a large hydrophobic side        chain; X⁷⁶ can be selected from an amino acid; X⁷⁷ can be        selected from a small hydrophobic side chain; X⁷⁸ can be        selected from an amino acid comprising a large hydrophobic side        chain; X⁷⁹ can be selected from an amino acid comprising a basic        side chain, an acidic side chain, or a polar-neutral side chain;        X⁸⁰ can be selected from an amino acid comprising a large        hydrophobic side chain; X⁸¹ can be selected from an amino acid        comprising a large hydrophobic side chain; and X⁸² can be        selected from an amino acid.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷¹ can be selected from anamino acid comprising a large hydrophobic side chain; X⁷² can beselected from an amino acid comprising an acidic side chain or a largehydrophobic side chain; X⁷³ can be selected from an amino acidcomprising an acidic side chain, a hydroxyl-containing side chain, or apolar neutral side chain; X⁷⁴ can be selected from an amino acidcomprising an acidic side chain, a hydroxyl-containing side chain, or alarge hydrophobic side chain; X⁷⁵ can be selected from an amino acidcomprising a large hydrophobic side chain; X⁷⁶ can be selected from anamino acid comprising an acidic side chain, a hydroxyl-containing sidechain, or a polar neutral side chain; X⁷⁷ can be selected from a smallhydrophobic side chain; X⁷⁸ can be selected from an amino acidcomprising a large hydrophobic side chain; X⁷⁹ can be selected from anamino acid comprising a basic side chain, an acidic side chain, or apolar-neutral side chain; X⁸⁰ can be selected from an amino acidcomprising a large hydrophobic side chain; X⁸¹ can be selected from anamino acid comprising a large hydrophobic side chain; and X⁸² can beselected from an amino acid comprising a polar neutral side chain.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷¹ can be selected from F,I, L, M, V, Y, and W; X⁷² can be selected from D, E, F, I, L, M, V, Y,and W; X⁷³ can be selected from D, E, S, T, H, N, Q, S, T, and Y; X⁷⁴can be selected from D, E, S, T, F, I, L, M, V, Y, and W; X⁷⁵ can beselected from F, I, L, M, V, Y, and W; X⁷⁶ can be selected from D, E, S,T, H, N, Q, S, T, and Y; X⁷⁷ can be selected from A, G, P, S, and T; X⁷⁸can be selected from F, I, L, M, V, Y, and W; X⁷⁹ can be selected fromR, K, H, D, E, H, N, Q, S, T, and Y; X⁸⁰ can be selected from F, I, L,M, V, Y, and W; X⁸¹ can be selected from F, I, L, M, V, Y, and W; andX⁸² can be selected from H, N, Q, S, T, and Y.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷¹ can be selected from I,L, and V.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷² can be selected from D,E, I, M, and V.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷³ can be selected from E,N, and Q.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁴ can be selected from Dand E.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁵ can be selected from F,W, and Y.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁶ can be selected from D,E, and N.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁷ can be G.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁸ can be selected from I,M, and V.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷⁹ can be selected from D,E, N, Q, and R.

In IL-2Rγc ligands of Formula (5) and (5a), X⁸⁰ can be selected from F,I, and L.

In IL-2Rγc ligands of Formula (5) and (5a), X⁸¹ can be W.

In IL-2Rγc ligands of Formula (5) and (5a), X⁸² can be selected from Nand Q.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷¹ can be selected from I,L, and V; X⁷² can be selected from D, E, I, M, and V; X⁷³ can beselected from E, N, and Q; X⁷⁴ can be selected from D and E; X⁷⁵ can beselected from F, W, and Y; X⁷⁶ can be selected from D, E, and N; X⁷⁷ canbe G; X⁷⁸ can be selected from I, M, and V; X⁷⁹ can be selected from D,E, N, Q, and R; X⁸⁰ can be selected from F, I, and L; X⁸¹ can be W; andX⁸² can be selected from N and Q.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷¹ can be selected from F,G, I, L, P, Q, R, T, and V; X⁷² can be selected from A, D, E, I, M, L,M, R, S, T, and V; X⁷³ can be selected from D, E, F, M, N, Q, S, T, V,W, and Y; X⁷⁴ can be selected from D, E, F, G, I, L, M, P, R, S, T, andV; X⁷⁵ can be selected from F, H, L, W, and Y; X⁷⁶ can be selected fromD, E, H, L, N, Q, S, and T; X⁷⁷ can be selected from E, G, Q, and T; X⁷⁸can be selected from I, L, M, Q, and V; X⁷⁹ can be selected from D, E,N, Q, and R; X⁸⁰ can be selected from D, F, I, and L; X⁸¹ can beselected from C, F, I, L, Q, R, T, W, and Y; and X⁸² can be selectedfrom A, F, G, H, I, L, N, P, Q, S, T, and W.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷¹ can be selected from F,I, L, and V; X⁷² can be selected from D, E, I, S, T, and V; X⁷³ can beselected from D, E, N, and Q; X⁷⁴ can be selected from D, E, F, I, L, M,and V; X⁷⁵ can be selected from F, W, and Y; X⁷⁶ can be selected from D,E, N, and Q; X⁷⁷ can be G; X⁷⁸ can be selected from I, L, M, and V; X⁷⁹can be selected from D, E, N, Q, and R; X⁸⁰ can be selected from D, F,I, and L; X⁸¹ can be selected from F, I, L, and W; and X⁸² can beselected from F, I, L, N, Q, and W.

In IL-2Rγc ligands of Formula (5) and (5a), X⁷¹ can be selected from F,I, L, and V; X⁷² can be selected from D, E, I, S, T, and V; X⁷³ can beselected from D, E, N, and Q; X⁷⁴ can be selected from D, E, F, I, L, M,and V; X⁷⁵ can be W; X⁷⁶ can be selected from D, E, N, and Q; X⁷⁷ can beG; X⁷⁸ can be V; X⁷⁹ can be selected from D, E, N, Q, and R; X⁸⁰ can beL; X⁸¹ can be W; and X⁸² can be selected from F, I, L, N, Q, and W.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 213 to SEQ ID NO: 233 and SEQ ID NO: 914 to SEQ ID NO:920:

SEQ ID NO: 213 I E C E F W D G M Q L C W Q SEQ ID NO: 214Q I C Q E W S G V N L C W H SEQ ID NO: 215 I L C Q D W S G I E I C W SSEQ ID NO: 216 L I C Y T Y E G V E L C W Q SEQ ID NO: 217L V C S M F N G V D L C W Q SEQ ID NO: 218 P R C E I W L G V E L C R ISEQ ID NO: 219 T E C Q V W N G V E L C Y I SEQ ID NO: 220V D C V I W E G V Q L C T W SEQ ID NO: 221 V V C T D Y L G V Q L C W TSEQ ID NO: 222 V M C E R W Q G V E L C W L SEQ ID NO: 223V V C Q G W S G V D I C W Q SEQ ID NO: 224 D C S M W E G V E L C WSEQ ID NO: 225 I V C E E W S G V R F C W N SEQ ID NO: 226Q T C W D Y E G M E L C L I SEQ ID NO: 227 P A C Q D W N G V E L C I LSEQ ID NO: 228 Q E C T D W Q G V E L C L L SEQ ID NO: 229R I C N D W N G V Q L C W P SEQ ID NO: 230 V I C Q S Y D G V E F C W FSEQ ID NO: 231 V V C E M Y S G V Q I C W A SEQ ID NO: 232L D C M D Y N G V R L C W N SEQ ID NO: 233 F T C W D Y N G V D L C Q ISEQ ID NO: 914 F S C F I L E T L E L A C W P SEQ ID NO: 915G A C N P H T Q Q E D C F G SEQ ID NO: 916 I E C Q V F H G L E L C W ISEQ ID NO: 917 V M C E L F D E V E L C W F SEQ ID NO: 918F V C E L W D G I E L C I P SEQ ID NO: 919 L T C V T Y E G V D L C W QSEQ ID NO: 920 V E C D V Y H G V E I C W A

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 211 to SEQ ID NO: 233 and SEQ ID NO: 914 to SEQ ID NO:920 and SEQ ID NOS 1071-1074, wherein the amino acid sequence can beterminated with amino acids -G-G- on the N-terminus, on the C-terminus,or on both the N- and C-termini.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 211 to SEQ ID NO: 233 and SEQ ID NO: 914 to SEQ ID NO:920 and SEQ ID NOS 1071-1074, wherein each amino acid independentlycomprises one or more of the following conservative substitutions: aminoacids having a small hydrophobic side chain comprising alanine (A),glycine (G), proline (P), serine (S), or threonine (T); amino acidshaving a hydroxyl-containing side chain comprising serine (S), threonine(T), or tyrosine (Y); amino acids having an acidic side chain comprisingaspartate (D) or glutamate (E); amino acids having a polar-neutral sidechain comprising histidine (H), asparagine (N), glutamine (Q), serine(S), threonine (T), or tyrosine (Y); amino acids having a basic sidechain comprising arginine (R), lysine (K), or histidine (H); amino acidshaving a large hydrophobic side chain comprising isoleucine (I), leucine(L), methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rγc ligands of SEQ ID NO: 211 to SEQ ID NO: 233 and SEQ ID NO: 914to SEQ ID NO: 920 and SEQ ID NOS 1071-1074, exhibit a binding affinity(IC₅₀) to the IL-2Rγc subunit of less than 100 μM.

An IL-2Rγc ligand can comprise the amino acid sequence of Formula (6)(SEQ ID NO: 234) or Formula (6a) (SEQ ID NO: 235):

—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰—X¹⁰¹—  (6)

—X⁹¹—X⁹²—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰—X¹⁰¹—X¹⁰²—X¹⁰³—  (6a)

-   -   wherein, X⁹¹ can be selected from C, D, E, and L; X⁹² can be        selected from C, L, M, R, S, V, and W; X⁹³ can be selected from        C, D, F, P, and R; X⁹⁴ can be selected from A, D, L, Q, S, and        W; X⁹⁵ can be selected from D, E, F, L, and V; X⁹⁶ can be        selected from A, D, E, F, G, K, Q, and S; X⁹⁷ can be selected        from E, L, M, and W; X⁹⁸ can be selected from G, I, L, W, and Y;        X⁹⁹ can be selected from E, I, R, T, and V; X¹⁰⁰ can be W; X¹⁰¹        can be selected from C, A, I, L, P, and V; X¹⁰² can be selected        from C, D, G, H; and X¹⁰³ can be selected from C, D, E, H, S,        and T.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹¹ can be selected from Dand E.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹² can be selected from L,M, R, S, V, and W.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹³ can be selected from Dand F.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁴ can be S.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁵ can be selected from Dand E.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁶ can be selected from Dand E.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁷ can be selected from L,M, and W.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁸ can be G.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁹ can be E.

In IL-2Rγc ligands of Formula (6) and (6a), X¹⁰⁰ can be W.

In IL-2Rγc ligands of Formula (6) and (6a), X¹⁰¹ can be selected from I,L, and V.

In IL-2Rγc ligands of Formula (6) and (6a), X¹⁰² can be selected from Dand G.

In IL-2Rγc ligands of Formula (6) and (6a), X¹⁰³ can be selected from Sand T.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹¹ can be selected from Dand E; X⁹² can be selected from L, M, R, S, V, and W; X⁹³ can beselected from D and F; X⁹⁴ can be S; X⁹⁵ can be selected from D and E;X⁹⁶ can be selected from D and E; X⁹⁶ can be selected from L, M, and W;X⁹⁸ can be G; X⁹⁹ can be E; X¹⁰⁰ can be W; X¹⁰¹ can be selected from I,L, and V; X¹⁰² can be selected from D and G; and X¹⁰³ can be selectedfrom S and T.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 236 to SEQ ID NO: 245:

SEQ ID NO: 236 M C W L E W G E W V G S C L SEQ ID NO: 237L C F S E F L G E W V D C SEQ ID NO: 238 V C S F D E A W G E W I C ESEQ ID NO: 239 D C P Q V S W Y E W L D C Y SEQ ID NO: 240Y C L F D E Q M G E W L C H SEQ ID NO: 241 C E S F S E A L G T W I D CSEQ ID NO: 242 C V F L E D W W I W A G D C SEQ ID NO: 243E C D A F G W I I W P H C L SEQ ID NO: 244 F C W D S D K M L R W V C SSEQ ID NO: 245 Q C R R S D F E Y V W L C T

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 234 to SEQ ID NO: 245 and SEQ ID NOS 1075-1076,wherein the amino acid sequence can be terminated with amino acids -G-G-on the N-terminus, on the C-terminus, or on both the N- and C-termini.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 234 to SEQ ID NO: 245 and SEQ ID NOS 1075-1076,wherein each amino acid independently comprises one or more of thefollowing conservative substitutions: amino acids having a smallhydrophobic side chain comprising alanine (A), glycine (G), proline (P),serine (S), or threonine (T); amino acids having a hydroxyl-containingside chain comprising serine (S), threonine (T), or tyrosine (Y); aminoacids having an acidic side chain comprising aspartate (D) or glutamate(E); amino acids having a polar-neutral side chain comprising histidine(H), asparagine (N), glutamine (Q), serine (S), threonine (T), ortyrosine (Y); amino acids having a basic side chain comprising arginine(R), lysine (K), or histidine (H); amino acids having a largehydrophobic side chain comprising isoleucine (I), leucine (L),methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rγc ligands of SEQ ID NO: 234 to SEQ ID NO: 245 and SEQ ID NOS1075-1076 exhibit a binding affinity (IC₅₀) to the IL-2Rγc subunit ofless than 100 μM.

An IL-2Rγc ligand can comprise the amino acid sequence of Formula (6)(SEQ ID NO: 1075) or Formula (6a) (SEQ ID NO: 1076):

—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰—X¹⁰¹—  (6)

—X⁹⁷—X⁹²—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰-X₁₀₁—X¹⁰²—X¹⁰³—  (6a)

-   -   wherein, X⁹¹ can be selected from an amino acid comprising an        acidic side chain or cysteine; X⁹² can be selected from an amino        acid; X⁹⁶ can be selected from an amino acid comprising an        acidic side chain or large hydrophobic side chain; X⁹⁴ can be        selected from an amino acid; X⁹⁵ can be selected from an amino        acid; X⁹⁶ can be selected from an amino acid; X⁹⁶ can be        selected from an amino acid comprising a large hydrophobic side        chain; X⁹⁸ can be selected from an amino acid comprising a small        hydrophobic side chain or a large hydrophobic side chain; X⁹⁹        can be selected from an amino acid; X¹⁰⁰ can be selected from an        amino acid comprising a large hydrophobic side chain; X¹⁰¹ can        be selected from an amino acid comprising a large hydrophobic        side chain; X¹⁰² can be selected from an amino acid comprising a        small hydrophobic side chain or an acidic side chain or        cysteine; and X¹⁰³ can be selected from an amino acid comprising        an acidic side chain or a hydroxyl-containing side chain or        cysteine.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹¹ can be selected from anamino acid comprising an acidic side chain; X⁹² can be selected from anamino acid; X⁹³ can be selected from an amino acid comprising an acidicside chain or large hydrophobic side chain; X⁹⁴ can be selected from anamino acid comprising an acidic side chain or a hydroxyl-containing sidechain; X⁹⁵ can be selected from an amino acid comprising an acidic sidechain; X⁹⁶ can be selected from an amino acid; X⁹⁷ can be selected froman amino acid comprising a large hydrophobic side chain; X⁹⁸ can beselected from an amino acid comprising a small hydrophobic side chain ora large hydrophobic side chain; X⁹⁹ can be selected from an amino acidcomprising an acidic side chain or large hydrophobic side chain; X¹⁰⁰can be selected from an amino acid comprising a large hydrophobic sidechain; X¹⁰¹ can be selected from an amino acid comprising a largehydrophobic side chain; X¹⁰² can be selected from an amino acidcomprising a small hydrophobic side chain or an acidic side chain; andX¹⁰³ can be selected from an amino acid comprising an acidic side chainor a hydroxyl-containing side chain.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹¹ can be selected from Dand E; X⁹² can be selected from an amino acid; X⁹³ can be selected fromD, E, F, I, L, M, V, Y, and W; X⁹⁴ can be selected from D, E, S, and T;X⁹⁵ can be selected from D and E; X⁹⁶ can be selected from an aminoacid; X⁹⁷ can be selected from F, I, L, M, V, Y, and W; X⁹⁸ can beselected from A, G, P, S, T, F, I, L, M, V, Y, and W; X⁹⁹ can beselected from D, E, F, I, L, M, V, Y, and W; X¹⁰⁰ can be selected fromF, I, L, M, V, Y, and W; X¹⁰¹ can be selected from F, I, L, M, V, Y, andW; X¹⁰² can be selected from D, E, A, G, P, S, and T; and X¹⁰³ can beselected from D, E, S, and T.

In IL-2Rγc ligands of Formula (6)-(6a), X⁹¹ can be selected from D andE.

In IL-2Rγc ligands of Formula (6)-(6a), X⁹² can be selected from anamino acid.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹³ can be selected from Dand F.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁴ can be S.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁵ can be selected from Dand E.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁶ can be selected from anamino acid.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁷ can be selected from L,M, and W.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁸ can be G.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹⁹ can be E.

In IL-2Rγc ligands of Formula (6) and (6a), X¹⁰⁰ can be W.

In IL-2Rγc ligands of Formula (6) and (6a), X¹⁰¹ can be selected from I,L, and V.

In IL-2Rγc ligands of Formula (6) and (6a), X¹⁰² can be selected from Dand G.

In IL-2Rγc ligands of Formula (6) and (6a), X¹⁰³ can be selected from Sand T.

In IL-2Rγc ligands of Formula (6) and (6a), X⁹¹ can be selected from Dand E; X⁹² can be selected from an amino acid; X⁹³ can be selected fromD and F; X⁹⁴ can be S; X⁹⁵ can be selected from D and E; X⁹⁶ can beselected from an amino acid; X⁹⁷ can be selected from L, M, and W; X⁹⁸can be G; X⁹⁹ can be E; X¹⁰⁰ can be W; X¹⁰¹ can be selected from I, L,and V; X¹⁰² can be selected from D and G; and X¹⁰³ can be selected fromS and T.

An IL-2Rγc ligand can comprise the amino acid sequence of Formula (7)(SEQ ID NO: 246) or Formula (7a) (SEQ ID NO: 247):

—X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹⁷—X¹¹⁸—  (7)

—X¹¹¹—X¹¹²—X¹¹³—X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹¹⁷—X¹¹⁸—X¹¹⁹—X¹²⁰—X¹²¹—  (7a)

-   -   wherein, X¹¹¹ can be selected from D, G, I, and Q; X¹¹² can be        selected from D, I, and L; X¹¹³ can be selected from G, L, M, Q,        R, S, and Y; X¹¹⁴ can be selected from D, E, G, L, S, T, and Y;        X¹¹⁵ can be selected from E, L, P, and Q; X¹¹⁶ can be selected        from D, E, K, L, S, and T; X¹¹⁷ can be selected from D, F, S,        and W; X¹¹⁸ can be selected from F, N, W, and Y; X¹¹⁹ can be        selected from F, I, L, R, and W; X¹¹²⁰ can be selected from A,        E, L, and S; and X¹²¹ can be selected from H I, K, N, Q, and V.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹¹ can be selected from Dand Q.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹² can be selected from Iand L.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹³ can be selected from G,L, M, R, S, and Y.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁴ can be L.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁵ can be selected from Eand Q.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁶ can be selected from Dand E.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁷ can be selected from Fand W.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁸ can be selected from F,W, and Y.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁹ can be selected from F,I, and L.

In IL-2Rγc ligands of Formula (7) and (7a), X¹²⁰ can be S.

In IL-2Rγc ligands of Formula (7) and (7a), X¹²¹ can be selected from Nand Q.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹¹ can be selected from Dand Q; X¹¹² can be selected from I and L; X¹¹³ can be selected from G,L, M, R, S, and Y; X¹¹⁴ can be L; X¹¹⁵ can be selected from E and Q;X¹¹⁶ can be selected from D and E; X¹¹⁷ can be selected from F and W;X¹¹⁸ can be selected from F, W, and Y; X¹¹⁹ can be selected from F, I,and L; X¹²⁰ can be S; and X¹²¹ can be selected from N and Q.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹¹ can be selected from D,G, I, Q, and W; X¹¹² can be selected from C, D, I, and L; X¹¹³ can beselected from G, L, M, Q, R, S, and Y; X¹¹⁴ can be selected from D, E,G, L, Q, S, T, and Y; X¹¹⁵ can be selected from E, G, L, P, and Q; X¹¹⁶can be selected from D, E, K, L, S, and T; X¹¹⁷ can be selected from D,F, S, and W; X¹¹⁸ can be selected from F, N, W, and Y; X¹¹⁹ can beselected from F, I, L, R, and W; X¹²⁰ can be selected from A, C, E, L,and S; and X¹²¹ can be selected from H, I, K, N, Q, and V.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹¹ can be selected from Dand Q; X¹¹² can be selected from I and L; X¹¹³ can be selected from G,L, M, Q, R, S, and Y; X¹¹⁴ can be selected from D and S; X¹¹⁵ can be L;X¹¹⁶ can be selected from D and E; X¹¹⁷ can be selected from F and W;X¹¹⁸ can be selected from F, W, and Y; X¹¹⁹ can be selected from F, I,L, and W; X¹²⁰ can be selected from L and S; and X¹²¹ can be selectedfrom N and Q.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 248 to SEQ ID NO: 254 and SEQ ID NO: 921 to SEQ ID NO:922 and SEQ ID NO: 1051:

SEQ ID NO: 248 D L S D L C T F W L S Q SEQ ID NO: 249G L Q E L C S F Y I A Q SEQ ID NO: 250 Q I R Q L C E F W L s QSEQ ID NO: 251 Q L G T L C D F F R E N SEQ ID NO: 252W C L S Q E E F N F L V SEQ ID NO: 253 Y S E E L S W I C K Q LSEQ ID NO: 254 I D M Y P Q E W W F C N SEQ ID NO: 921L S L G Q K D W W L I L SEQ ID NO: 922 Q L Q G L C D F F W A H

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 246 to SEQ ID NO: 254 and SEQ ID NO: 921 to SEQ ID NO:922 and SEQ ID NOS 1051 and 1077-1082, wherein the amino acid sequencecan be terminated with amino acids -G-G- on the N-terminus, on theC-terminus, or on both the N- and C-termini.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 246 to SEQ ID NO: 254 and SEQ ID NO: 921 to SEQ ID NO:922 and SEQ ID NOS 1051 and 1077-1082, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rγc ligands of SEQ ID NO: 246 to SEQ ID NO: 254 and and SEQ ID NO:921 to SEQ ID NO: 922 and SEQ ID NOS 1051 and 1077-1082 exhibit abinding affinity (IC₅₀) to the IL-2Rγc subunit of less than 100 μM.

An IL-2Rγc ligand can comprise the amino acid sequence of Formula (7)(SEQ ID NO: 1077) or Formula (7a) (SEQ ID NO: 1078):

X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹¹⁷—X¹¹⁸—  (7)

X¹¹¹—X¹¹²—X¹¹³—X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹¹⁷—X¹¹⁸—X¹¹⁹—X¹²⁰—X¹²¹—  (7a)

-   -   wherein, X¹¹¹ can be selected from an amino acid; X¹¹² can be        selected from an amino acid comprising a large hydrophobic side        chain or an acidic side chain; X¹¹³ can be selected from an        amino acid; X¹¹⁴ can be selected from an amino acid comprising        an acidic side chain or a hydroxyl-containing side chain; X¹¹⁵        can be selected from an amino acid; X¹¹⁶ can be selected from an        amino acid; X¹¹⁷ can be selected from an amino acid comprising a        large hydrophobic side chain; X¹¹⁸ can be selected from an amino        acid comprising a large hydrophobic side chain; X¹¹⁹ can be        selected from an amino acid comprising a large hydrophobic side        chain; X¹²⁰ can be selected from an amino acid; and X¹²¹ can be        selected from an amino acid.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹¹ can be selected from anamino acid; X¹¹² can be selected from an amino acid comprising a largehydrophobic side chain or an acidic side chain; X¹¹³ can be selectedfrom an amino acid; X¹¹⁴ can be selected from an amino acid comprisingan acidic side chain or a hydroxyl-containing side chain; X¹¹⁵ can beselected from an amino acid comprising a large hydrophobic side chain;X¹¹⁶ can be selected from an amino acid comprising an acidic side chain;X¹¹⁷ can be selected from an amino acid comprising a large hydrophobicside chain; X¹¹⁸ can be selected from an amino acid comprising a largehydrophobic side chain; X¹¹⁹ can be selected from an amino acidcomprising a large hydrophobic side chain; X¹²⁰ can be selected from anamino acid; and X¹²¹ can be selected from an amino acid comprising apolar-neutral side chain.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹¹ can be selected from anamino acid; X¹¹² can be selected from D, E, F, I, L, M, V, Y, and W;X¹¹³ can be selected from an amino acid; X¹¹⁴ can be selected from D, E,S, and T; X¹¹⁵ can be selected from F, I, L, M, V, Y, and W; X¹¹⁶ can beselected from D and E; X¹¹⁷ can be selected from F, I, L, M, V, Y, andW; X¹¹⁸ can be selected from F, I, L, M, V, Y, and W; X¹¹⁹ can beselected from F, I, L, M, V, Y, and W; X¹²⁰ can be selected from anamino acid; and X¹²¹ can be selected from H, N, Q, S, T, and Y.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹¹ can be selected from anamino acid.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹² can be selected from Iand L.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹³ can be selected from anamino acid.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁴ can be selected from D,E, and S.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁵ can be L.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁶ can be selected from Dand E.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁷ can be selected from Fand W.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁸ can be selected from F,W and Y.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹⁹ can be selected from F,I, and L.

In IL-2Rγc ligands of Formula (7) and (7a), X¹²⁰ can be selected from anamino acid.

In IL-2Rγc ligands of Formula (7) and (7a), X¹²¹ can be selected from Qand N.

In IL-2Rγc ligands of Formula (7) and (7a), X¹¹¹ can be selected from anamino acid; X¹¹² can be selected from I and L; X¹¹³ can be selected froman amino acid; X¹¹⁴ can be selected from D, E, and S; X¹¹⁵ can be L;X¹¹⁶ can be selected from D and E; X¹¹⁷ can be selected from F and W;X¹¹⁸ can be selected from F, W and Y; X¹¹⁹ can be selected from F, I,and L; X¹²⁰ can be selected from an amino acid; and X¹²¹ can be selectedfrom Q and N.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 255 to SEQ ID NO: 264 and SEQ ID NO: 923 to SEQ ID NO:930:

SEQ ID NO: 255 C P L S L M G S E R I F V C SEQ ID NO: 256C T Y F G P D A F R M L F C SEQ ID NO: 257 C Y F N S I F L G E S P F CSEQ ID NO: 258 C Y L I Y K N N Q L A L Q C SEQ ID NO: 259C Y V V Y N Y Q E F R Y L C SEQ ID NO: 260 L Y C R D N D G T Q Y C E TSEQ ID NO: 261 Y Y C Y L N I W T M K C E D SEQ ID NO: 262Y Y C Y L N I W P V K C E D SEQ ID NO: 263 L E C A T S E E P Y Y C Y LSEQ ID NO: 264 C D C Q H H R C R T G G L V SEQ ID NO: 923L F N F C Q G D K T C M Q W H SEQ ID NO: 924E C G G A W A M L L W P H C T SEQ ID NO: 925I C T R L H D V V P I W S C P SEQ ID NO: 926Q C Y R P S R D I P L Y L C S SEQ ID NO: 927L F N F C Q G D K T C M Q W H SEQ ID NO: 928 V C W L T H N R Q S Y Y C DSEQ ID NO: 929 C D L W P L T A Q N F Y G C SEQ ID NO: 930C P G E L R G P E R A W V C

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 255 to SEQ ID NO: 264 and SEQ ID NO: 923 to SEQ ID NO:930, wherein the amino acid sequence can be terminated with amino acids-G-G- on the N-terminus, on the C-terminus, or on both the N- andC-termini.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 255 to SEQ ID NO: 264 and SEQ ID NO: 923 to SEQ ID NO:930, wherein each amino acid independently comprises one or more of thefollowing conservative substitutions: amino acids having a smallhydrophobic side chain comprising alanine (A), glycine (G), proline (P),serine (S), or threonine (T); amino acids having a hydroxyl-containingside chain comprising serine (S), threonine (T), or tyrosine (Y); aminoacids having an acidic side chain comprising aspartate (D) or glutamate(E); amino acids having a polar-neutral side chain comprising histidine(H), asparagine (N), glutamine (Q), serine (S), threonine (T), ortyrosine (Y); amino acids having a basic side chain comprising arginine(R), lysine (K), or histidine (H); amino acids having a largehydrophobic side chain comprising isoleucine (I), leucine (L),methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rγc ligands of SEQ ID NO: 255 to SEQ ID NO: 264 and SEQ ID NO: 923to SEQ ID NO: 930 exhibit a binding affinity (IC₅₀) to the IL-2Rγcsubunit of less than 100 μM.

An IL-2Rγc ligand can comprise the amino acid sequence of Formula (8)(SEQ ID NO: 931):

—C—X¹³¹—X¹³²—X¹³³—X¹³⁴—X¹³⁵—X¹³⁶—X¹³⁷—X¹³⁸—X¹³⁹—X¹⁴⁰—X¹⁴¹—X¹⁴²—C—  (8)

-   -   wherein, X¹³¹ can be selected from an amino acid comprising a        large hydrophobic side chain; X¹³² can be selected from an amino        acid comprising a large hydrophobic side chain; X¹³³ can be        selected from an amino acid comprising a large hydrophobic side        chain; X¹³⁴ can be selected from an amino acid comprising a        large hydrophobic side chain or an aromatic side chain; X¹³⁵ can        be selected from an amino acid comprising a basic side chain and        an acidic or polar neutral side chain; X¹³⁶ can be selected from        an amino acid; X¹³⁷ can be selected from an amino acid        comprising a small hydrophobic side chain; X¹³⁸ can be selected        from an amino acid comprising an acidic or a polar neutral side        chain; X¹³⁹ can be selected from an amino acid comprising a        large hydrophobic side chain or an aromatic side chain; X¹⁴⁰ can        be selected from an amino acid comprising a small hydrophobic        side chain or a hydroxyl-containing side chain; X¹⁴¹ can be        selected from an amino acid comprising a large hydrophobic side        chain or an aromatic side chain; and X¹⁴² can be selected from        an amino acid comprising a large hydrophobic side chain.

In IL-2Rγc ligands of Formula (8), X¹³¹ can be selected from F, I, L, M,V, Y, and W; X¹³² can be selected from F, I, L, M, V, Y, and W; X¹³³ canbe selected from F, I, L, M, V, Y, and W; X¹³⁴ can be selected from F,H, I, L, M, V, Y, and W; X¹³⁵ can be selected from R, K, H, D, E, N, andQ; X¹³⁶ can be selected from an amino acid; X¹³⁷ can be selected from A,G, P, S, and T; X¹³⁸ can be selected from D, E, N, and Q; X¹³⁹ can beselected from F, H, I, L, M, V, Y, and W; X¹⁴⁰ can be selected from A,G, P, S, T, and Y; X¹⁴¹ can be selected from F, H, I, L, M, V, Y, and W;and X¹⁴² can be selected from F, I, L, M, V, Y, and W.

In IL-2Rγc ligands of Formula (8), X¹³¹ can be selected from F and Y;X¹³² can be I; X¹³³ can be selected from F, I, L, M, V, Y, and W; X¹³⁴can be Y; X¹³⁵ can be R; X¹³⁶ can be selected from an amino acid; X¹³⁷can be G; X¹³⁸ can be E; X¹³⁹ can be F; X¹⁴⁰ can be selected from S, T,and Y; X¹⁴¹ can be Y; and X¹⁴² can be selected from F, I, L, M, V, Y,and W.

In IL-2Rγc ligands of Formula (8), X¹³¹ can be selected from F and Y.

In IL-2Rγc ligands of Formula (8), X¹³² can be selected from I, V, andL.

In IL-2Rγc ligands of Formula (8), X¹³² can be I.

In IL-2Rγc ligands of Formula (8), X¹³³ can be selected from M, L, Y,and I.

In IL-2Rγc ligands of Formula (8), X¹³⁴ can be selected from F, H, andY.

In IL-2Rγc ligands of Formula (8), X¹³⁵ can be Y.

In IL-2Rγc ligands of Formula (8), X¹³⁶ can be selected from R, K, D,and E.

In IL-2Rγc ligands of Formula (8), X¹³⁷ can be R.

In IL-2Rγc ligands of Formula (8), X¹³⁶ can be selected from an aminoacid.

In IL-2Rγc ligands of Formula (8), X¹³⁷ can be G.

In IL-2Rγc ligands of Formula (8), X¹³⁷ can be selected from D and E.

In IL-2Rγc ligands of Formula (8), X¹³⁸ can be E.

In IL-2Rγc ligands of Formula (8), X¹³⁹ can be selected from F, Y, andW.

In IL-2Rγc ligands of Formula (8)), X¹³⁹ can be F.

In IL-2Rγc ligands of Formula (8), X¹⁴⁰ can be selected from S and T.

In IL-2Rγc ligands of Formula (8), X⁴¹ can be selected from F, I, L, M,V, Y, and W.

In IL-2Rγc ligands of Formula (8), X¹⁴¹ can be Y.

In IL-2Rγc ligands of Formula (8), X¹⁴² can be selected from I, L, M, V,and Y.

In IL-2Rγc ligands of Formula (8), X¹³¹ can be selected from F and Y;X¹³² can be I; X¹³³ can be selected from M, L, Y, and I; X¹³⁴ can be Y;X¹³⁵ can be R; X¹³⁶ can be selected from an amino acid; X¹³⁷ can be G;X¹³⁸ can be E; X¹³⁹ can be F; X¹⁴⁰ can be selected from S and T; X¹⁴¹can be Y; and X¹⁴² can be selected from F, I, L, M, V, Y, and W.

In IL-2Rγc ligands of Formula (8), X¹³¹ can be selected A, C, D, E, F,G, L, P, and Y; X¹³² can be selected from C, I, L, N, S, and V; X¹³³ canbe selected from A, I, L, M, Q, R, and Y; X¹³⁴ can be selected from F,H, K, L, T, and Y; X¹³⁵ can be selected from D, E, G, H, I, K, L, P, Q,R, S, and Y; X¹³⁶ can be selected from E, F, G, H, I, L, N, Q, R, S, andT; X¹³⁷ can be selected from C, D, E, G, K, N, P, Q, and T X¹³⁸ can beselected from D, E, F, K, P, R, and T; X¹³⁹ can be selected from A, F,L, R, T, V, W, and Y; X¹⁴⁰ can be selected from D, E, G, L, N, S, T, W,and Y; X¹⁴¹ can be selected from A, C, F, G, I, L, M, and Y; and X¹⁴²can be selected from C, E, I, L, M, V, and Y.

In IL-2Rγc ligands of Formula (8), X¹³¹ can be selected F and Y; X¹³²can be selected from I, L, and V; X¹³³ can be selected from I, M, R, andY; X¹³⁴ can be selected from F, H, and Y; X¹³⁵ can be selected from D,E, K, and R; X¹³⁶ can be selected from E, F, G, H, I, L, N, Q, R, S, andT; X¹³⁷ can be G; X¹³⁸ can be selected from D and E; X¹³⁹ can beselected from F, W, and Y; X¹⁴⁰ can be selected from S and T; X¹⁴¹ canbe selected from F, I, L, M, and Y; and X¹⁴² can be selected from I, L,M, V and Y.

In IL-2Rγc ligands of Formula (8), X¹³¹ can be F; X¹³² can be I; X¹³³can be selected from I, M, R, and Y; X¹³⁴ can be Y; X¹³⁵ can be selectedfrom D, E, K, and R; X¹³⁶ can be selected from E, F, G, H, I, L, N, Q,R, S, and T; X¹³⁷ can be G; X¹³⁸ can be E; X¹³⁹ can be F; X¹⁴⁰ can beselected from S and T; X¹⁴¹ can be Y; and X¹⁴² can be selected from I,L, M, V and Y.

In IL-2Rγc ligands of Formula (8), X¹³¹ can be F, X¹³² can be I, X¹³⁴can be Y, X¹²⁵ can be R, X¹³⁷ can be G, X¹³⁸ can be E, X¹³⁹ can be F,and X¹⁴¹ can be Y.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 265 to SEQ ID NO: 267 and SEQ ID NO: 932 to SEQ ID NO:940:

SEQ ID NO: 265 C G I A Y R S G E F T M I C SEQ ID NO: 266C P S M L Q G P E R T W V C SEQ ID NO: 267 W C I Y Y P F T D V E A C TSEQ ID NO: 932 C A N L H D T Q E W W Y Y C SEQ ID NO: 933C E L L T G I P E Y N F L C SEQ ID NO: 934 C F I R F Y Q D K Y D Y V CSEQ ID NO: 935 C F I R Y L R G E F S F V C SEQ ID NO: 936C F L R F I H G E L D Y Y C SEQ ID NO: 937 C F V M Y K N N E F S L I CSEQ ID NO: 938 C G I A Y R S G E F T M I C SEQ ID NO: 939C L I Y K E Q K F A L I E C SEQ ID NO: 940 C Y I I Y R L G T F S Y M C

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 265 to SEQ ID NO: 267 and SEQ ID NO: 931 to SEQ ID NO:940, and SEQ ID NO: 1083, wherein the amino acid sequence can beterminated with amino acids -G-G- on the N-terminus, on the C-terminus,or on both the N- and C-termini.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 265 to SEQ ID NO: 267 and SEQ ID NO: 931 to SEQ ID NO:940, and SEQ ID NO: 1083, wherein each amino acid independentlycomprises one or more of the following conservative substitutions: aminoacids having a small hydrophobic side chain comprising alanine (A),glycine (G), proline (P), serine (S), or threonine (T); amino acidshaving a hydroxyl-containing side chain comprising serine (S), threonine(T), or tyrosine (Y); amino acids having an acidic side chain comprisingaspartate (D) or glutamate (E); amino acids having a polar-neutral sidechain comprising histidine (H), asparagine (N), glutamine (Q), serine(S), threonine (T), or tyrosine (Y); amino acids having a basic sidechain comprising arginine (R), lysine (K), or histidine (H); amino acidshaving a large hydrophobic side chain comprising isoleucine (I), leucine(L), methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rγc ligands of SEQ ID NO: 265 to SEQ ID NO: 267 and SEQ ID NO: 931to SEQ ID NO: 940, and SEQ ID NO: 1083 exhibit a binding affinity (IC₅₀)to the IL-2Rγc subunit of less than 100 μM.

An IL-2Rγc ligand can comprise the amino acid sequence of Formula (9)(SEQ ID NO: 941) or the amino acid sequence of Formula 9a) (SEQ ID NO:942):

—X¹⁵⁵—X¹⁵⁶—X¹⁵⁷—X¹⁵⁸—X¹⁵⁹—  (9)

—X¹⁵¹—X¹⁵²—X¹⁵³—X¹⁵⁴—C—X¹⁵⁵—X¹⁵⁶—X¹⁵⁷—X¹⁵⁸—X¹⁵⁹—C—X¹⁶⁰—X¹⁶¹—X¹⁶²—X¹⁶³—  (9a)

wherein, X¹⁵¹ can be selected from an amino acid comprising a smallhydrophobic side chain or a hydroxyl-containing side chain; X¹⁵² can beselected from an amino acid comprising a large hydrophobic side chain;X¹⁵³ can be selected from an amino acid comprising an acidic or polarneutral side chain; X¹⁵⁴ can be selected from an amino acid comprising abasic side chain; X¹⁵⁵ can be selected from an amino acid comprising alarge hydrophobic side chain; X¹⁵⁶ can be selected from an amino acidcomprising a small hydrophobic side chain or a hydroxyl-containing sidechain; X¹⁵⁷ can be selected from an amino acid comprising a smallhydrophobic side chain; X¹⁵⁸ can be selected from an amino acidcomprising a small hydrophobic side chain or a hydroxyl-containing sidechain; X¹⁵⁹ can be selected from an amino acid comprising a smallhydrophobic side chain or a hydroxyl-containing side chain; X¹⁶⁰ can beselected from an amino acid comprising a small hydrophobic side chain ora hydroxyl-containing side chain; X¹⁶¹ can be selected from an aminoacid; X¹⁶² can be selected from an amino acid comprising a largehydrophobic side chain or a basic side chain; and X¹⁶³ can be selectedfrom an amino acid comprising a large hydrophobic side chain.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵¹ can be selectedfrom A, G, P, S, and T; X¹⁵² can be selected from F, I, L, M, V, Y, andW; X¹⁵³ can be selected from D, E, N, and Q; X¹⁵⁴ can be selected fromH, K, and R; X¹⁵⁵ can be selected from F, I, L, M, V, Y, and W; X¹⁵⁶ canbe selected from A, G, P, S, and T; X¹⁵⁷ can be selected from A, G, P,S, and T; X¹⁵⁸ can be selected from A, G, P, S, and T; X¹⁵⁹ can beselected from A, G, P, S, and T; X¹⁶⁰ can be selected from A, G, P, S,and T; X¹⁶¹ can be selected from an amino acid; X¹⁶² can be selectedfrom F, I, L, M, V, Y, W, R, K, and H; and X¹⁶³ can be selected from F,I, L, M, V, Y, and W.

In IL-2Rγc ligands of Formula (9) and Formula (9a). X¹⁵¹ can be selectedfrom K, M, N, and K; X¹⁵² can be selected from M, L, and Y; X¹⁵³ can beselected from N, Y, and L; X¹⁵⁴ can be K; X¹⁵⁵ can be selected from A,W, R, Y, and N; X¹⁵⁶ can be selected from T, N, and S; X¹⁵⁷ can beselected from P and A; X¹⁵⁸ can be selected from S, R, F, and L; X¹⁵⁹can be selected from Q, S, E, and T; X¹⁶⁰ can be selected from S, Q, andA; X¹⁶¹ can be selected from V, S, G, L, and N; X¹⁶² can be selectedfrom I, K, R, and V; and X¹⁶³ can be selected from F and L.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵¹ can be selectedfrom S and T.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵² can be selectedfrom L and M.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵² can be L.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵³ can be N.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵⁴ can be K.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵⁵ can be selectedfrom W and Y.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵⁶ can be selectedfrom S and T.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵⁶ can be S.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵⁷ can be P.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵⁸ can be S.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵⁹ can be selectedfrom S and T.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵⁹ can be S.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁶⁰ can be S.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁶¹ can be selectedfrom an amino acid.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁶² can be selectedfrom I, V, R, and K.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁶² can be selectedfrom I and V.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁶² can be selectedfrom R and K.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁶³ can be selectedfrom F and L.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁶³ can be L.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵¹ can be selectedfrom S and T; X¹⁵² can be L; X¹⁵³ can be N; X¹⁵⁴ can be K; X¹⁵⁵ can beselected from W and Y; X¹⁵⁶ can be S; X¹⁵⁷ can be P; X¹⁵⁸ can be S; X¹⁵⁹can be S; X¹⁶⁰ can be S T; X¹⁶¹ can be selected from an amino acid; X¹⁶²can be I; and X¹⁶³ can be F.

In IL-2Rγc ligands of Formula (9) and Formula (9a), X¹⁵² can be L, X¹⁵³can be N, X¹⁵⁴ can be K, X¹⁵⁶ can be S, X¹⁵⁷ can be P, X¹⁵⁸ can be S,X¹⁵⁹ can be S, X¹⁶⁰ can be S, X¹⁶² can be I, and X¹⁶³ can be F.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 943 to SEQ ID NO: 948:

SEQ ID NO: 943 K M N K C A T P S Q C S V I F SEQ ID NO: 944N L N K C W N P R S C S S K F SEQ ID NO: 945T Y N K C R S P F E C S G I F SEQ ID NO: 946Y L N K C Y S P S S C Q L R L SEQ ID NO: 947S L Y K C N S P L S C S N I F SEQ ID NO: 948S L L K C Y N A S T C A S V F

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 941 to SEQ ID NO: 948, wherein the amino acid sequencecan be terminated with amino acids -G-G- on the N-terminus, on theC-terminus, or on both the N- and C-termini.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 941 to SEQ ID NO: 948, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rγc ligands of SEQ ID NO: 941 to SEQ ID NO: 948 exhibit a bindingaffinity (IC₅₀) to the IL-2Rγc subunit of less than 100 μM.

An IL-2Rγc ligand can comprise the amino acid sequence of Formula (12)(SEQ ID NO: 949):

—X¹⁷¹—X¹⁷²—X¹⁷³—X¹⁷⁴—X¹⁷⁵—C—X¹⁷⁶—X¹⁷⁷—X¹⁷⁸—X¹⁷⁹—X¹⁸⁰—X¹⁸¹—X¹⁸²—X¹⁸³—C—X¹⁸⁴—X¹⁸⁵—X¹⁸⁶—X¹⁸⁷—X¹⁸⁸—  (12)

-   -   wherein, X¹⁷¹ can be selected from an amino acid comprising a        basic side chain; X¹⁷² can be selected from an amino acid        comprising a hydroxyl-containing side chain; X¹⁷³ can be        selected from an amino acid comprising an acidic side chain or a        large hydrophobic side chain; X¹⁷⁴ can be selected from an amino        acid comprising a large hydrophobic side chain; X¹⁷⁵ can be        selected from an amino acid comprising an acidic side chain or a        large hydrophobic side chain; X¹⁷⁶ can be selected from an amino        acid comprising an acidic side chain or a polar/neutral side        chain; X¹⁷⁷ can be selected from an amino acid comprising an        acidic side chain; X¹⁷⁸ can be selected from an amino acid        comprising a large hydrophobic side chain or an aromatic side        chain; X¹⁷⁹ can be selected from an amino acid comprising an        acidic side chain or a polar/neutral side chain; X¹⁸⁰ can be G;        X¹⁸¹ can be V; X¹⁸² can be E; X¹⁸³ can be L; X¹⁸⁴ can be W; X¹⁸⁵        can be selected from an amino acid comprising a large        hydrophobic side chain; X¹⁸⁶ can be E; X¹⁸⁷ can be selected from        an amino acid; and X¹⁸⁸ can be selected from an amino acid        comprising an acidic side chain.

In IL-2Rγc ligands of Formula (12), X¹⁷¹ can be selected from H, K, andR; X¹⁷² can be selected from S, T, and Y; X¹⁷³ can be selected from D,E, F, I, L, M, V, W, and Y; X¹⁷⁴ can be selected from F, I, L, M, V, W,and Y; X¹⁷⁵ can be selected from D, E, F, I, L, M, V, W, and Y; X¹⁷⁶ canbe selected from D, E, H, N, Q, S, T, and Y; X¹⁷⁷ can be selected from Dand E; X¹⁷⁸ can be selected from F, H, I, L, M, V, W, and Y; X¹⁷⁹ can beselected from D, E, H, N, Q, S, T, and Y; X¹⁸⁰ can be G; X¹⁸¹ can be V;X¹⁸² can be E; X¹⁸³ can be L; X¹⁸⁴ can be W; X¹⁸⁵ can be selected fromF, I, L, M, V, W, and Y; X¹⁸⁶ can be E; X¹⁸⁷ can be selected from anamino acid; and X¹⁸⁸ can be selected from D and E.

In IL-2Rγc ligands of Formula (12), X¹⁷¹ can be selected from D, E, G,H, K, M, N, P, Q, R, S, and T; X¹⁷² can be selected from A, D, E, G, I,K, L, P, Q, R, S, T, V, W, and Y; X¹⁷³ can be selected from A, D, E, F,G, I, Q, S, T, V, W, and Y; X⁷⁴ can be selected from A, I, E, I, L, M,N, Q, R, S, T, and V; X¹⁷⁵ can be selected from A, E, I, L, M, N, Q, R,S, T, and V; X¹⁷⁶ can be selected from D, E, H, L, Q, R, and V; X¹⁷⁷ canbe selected from D, E, N, T, and V; X¹⁷⁸ can be selected from F, S, W,and Y; X¹⁷⁹ can be selected from A, D, E, G, H, K, N, Q, R, and Y; X¹⁸⁰can be selected from G and R; X¹⁸¹ can be V; X¹⁸² can be selected fromD, E, and Y; X¹⁸³ can be selected from F, I, and L; X¹⁸⁴ can be W; X¹⁸⁵can be selected from C, H, I, L, P, Q, T, V, and Y; X¹⁸⁶ can be selectedfrom A, D, E, G, M, R, S, T, and V; X¹⁸⁷ can be selected from A, D, E,F, G, I, M, N, P, Q, R, S, T, V, W, and Y; and X¹⁸⁸ can be selected fromA, C, D, E, F, G, I, K, L, N, P, Q, R, S, and V.

In IL-2Rγc ligands of Formula (12), X¹⁷¹ can be selected from H, K, andR; X¹⁷² can be selected from S, T, and Y; X¹⁷³ can be selected from D,E, F, I, and V; X¹⁷⁴ can be selected from I and V; X¹⁷⁵ can be selectedfrom E, I, L, M, and V; X¹⁷⁶ can be selected from D, E, and Q; X¹⁷⁷ canbe selected from D and E; X¹⁷⁸ can be selected from F and W; X¹⁷⁹ can beselected from D, E, N, and Q; X¹⁸⁰ can be G; X¹⁸¹ can be V; X¹⁸² can beselected from D and E; X¹⁸³ can be L; X¹⁸⁴ can be W; X¹⁸⁵ can beselected from I, L, Q, and V; X¹⁸⁶ can be selected from D and E; X¹⁸⁷can be selected from A, D, E, F, G, I, M, N, P, Q, R, S, T, V, W, and Y;and X¹⁸⁸ can be selected from D, E, N, and Q.

In IL-2Rγc ligands of Formula (12), X¹⁷¹ can be selected from K and R;X¹⁷² can be selected from S, T, and Y; X¹⁷³ can be selected from D, E,F, I, and V; X¹⁷⁴ can be V; X¹⁷⁵ can be selected from E, L, M, and V;X¹⁷⁶ can be Q; X¹⁷⁷ can be selected from D and E; X¹⁷⁸ can be W; X¹⁷⁹can be selected from D, E, N, and Q; X¹⁸⁰ can be G; X¹⁸¹ can be V; X¹⁸²can be E; X¹⁸³ can be L; X¹⁸⁴ can be W; X¹⁸⁵ can be selected from I, L,Q, and V; X¹⁸⁶ can be selected from D and E; X¹⁸⁷ can be selected fromA, D, E, F, G, I, M, N, P, Q, R, S, T, V, W, and Y; and X¹⁸⁸ can beselected from D, E, N, and Q.

In IL-2Rγc ligands of Formula (12), X¹⁷¹ can be selected from H, K, andR.

In IL-2Rγc ligands of Formula (12), X¹⁷² can be selected from S, T, andY.

In IL-2Rγc ligands of Formula (12), X¹⁷³ can be selected from D, E, F,I, L, M, V, W, and Y.

In IL-2Rγc ligands of Formula (12), X¹⁷³ can be selected from D and E.

In IL-2Rγc ligands of Formula (12), X¹⁷³ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rγc ligands of Formula (12), X¹⁷⁴ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rγc ligands of Formula (12), X¹⁷⁴ can be V.

In IL-2Rγc ligands of Formula (12), X¹⁷⁵ can be selected from D, E, F,I, L, M, V, W, and Y.

In IL-2Rγc ligands of Formula (12), X¹⁷⁵ can be selected from D and E.

In IL-2Rγc ligands of Formula (12), X¹⁷⁵ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rγc ligands of Formula (12), X¹⁷⁶ can be selected from D, E, H,N, Q, S, T, and Y.

In IL-2Rγc ligands of Formula (12), X¹⁷⁶ can be selected from E and Q.

In IL-2Rγc ligands of Formula (12), X¹⁷⁷ can be selected from D and E.

In IL-2Rγc ligands of Formula (12), X¹⁷⁸ can be selected from F, H, I,L, M, V, W, and Y.

In IL-2Rγc ligands of Formula (12), X¹⁷⁸ can be selected from F, H, W,and Y.

In IL-2Rγc ligands of Formula (12), X¹⁷⁹ can be W.

In IL-2Rγc ligands of Formula (12), X¹⁷⁹ can be selected from D, E, H,N, Q, S, T, and Y.

In IL-2Rγc ligands of Formula (12), X⁷⁹ can be selected from D, E, andQ.

In IL-2Rγc ligands of Formula (12), X¹⁸⁰ can be G.

In IL-2Rγc ligands of Formula (12), X¹⁸¹ can be V.

In IL-2Rγc ligands of Formula (12), X¹⁸² can be E.

In IL-2Rγc ligands of Formula (12), X¹⁸³ can be L.

In IL-2Rγc ligands of Formula (12), X¹⁸⁴ can be W.

In IL-2Rγc ligands of Formula (12), X¹⁸⁵ can be selected from F, I, L,M, V, W, and Y.

In IL-2Rγc ligands of Formula (12), X¹⁸⁵ can be L.

In IL-2Rγc ligands of Formula (12), X¹⁸⁶ can be E.

In IL-2Rγc ligands of Formula (12), X¹⁸⁷ can be selected from an aminoacid.

In IL-2Rγc ligands of Formula (12), X¹⁸⁸ can be selected from D and E.

In IL-2Rγc ligands of Formula (12), X¹⁷¹ can be selected from H, K, andR; X¹⁷² can be selected from S, T, and Y; X¹⁷³ can be selected from D,E, F, I, L, M, V, W, and Y; X¹⁷⁴ can be selected from F, I, L, M, V, W,and Y; X¹⁷⁵ can be selected from D, E, F, I, L, M, V, W, and Y; X¹⁷⁶ canbe selected from D, E, H, N, Q, S, T, and Y; X¹⁷⁷ can be selected from Dand E; X¹⁷⁸ can be selected from F, H, I, L, M, V, W, and Y; X¹⁷⁹ can beselected from D, E, H, N, Q, S, T, and Y; X¹⁸⁰ can be G; X¹⁸¹ can be V;X¹⁸² can be E; X¹⁸³ can be L; X¹⁸⁴ can be selected from W; X¹⁸⁵ can beselected from F, I, L, M, V, W, and Y; X¹⁸⁶ can be E; X¹⁸⁷ can beselected from an amino acid; and X¹⁸⁸ can be selected from D and E.

In IL-2Rγc ligands of Formula (12), X¹⁷¹ can be selected from H, K, andR; X¹⁷² can be selected from S, T, and Y; X¹⁷³ can be selected from Dand E; X¹⁷⁴ can be V; X¹⁷⁵ can be selected from D and E; X¹⁷⁶ can beselected from E and Q; X¹⁷⁷ can be selected from D and E; X¹⁷⁸ can beselected from F, H, W, and Y; X¹⁷⁹ can be selected from D, E, and Q;X¹⁸⁰ can be G; X¹⁸¹ can be V; X¹⁸² can be E; X¹⁸³ can be L; X¹⁸⁴ can beW; X¹⁸⁵ can be selected from F, I, L, M, V, W, and Y; X¹⁸⁶ can be E;X¹⁸⁷ can be selected from an amino acid; and X¹⁸⁸ can be selected from Dand E.

In IL-2Rγc ligands of Formula (12), X¹⁷¹ can be selected from H, K, andR; X¹⁷² can be selected from S, T, and Y; X¹⁷³ can be selected from F,I, L, M, V, W, and Y; X¹⁷⁴ can be V; X¹⁷⁵ can be selected from F, I, L,M, V, W, and Y; X¹⁷⁶ can be selected from E and Q; X¹⁷⁷ can be selectedfrom D and E; X¹⁷⁸ can be selected from F, H, W, and Y; X¹⁷⁹ can beselected from D, E, and Q; X¹⁸⁰ can be G; X¹⁸¹ can be V; X¹⁸² can be E;X¹⁸³ can be L; X¹⁸⁴ can be W; X¹⁸⁵ can be selected from F, I, L, M, V,W, and Y; X¹⁸⁶ can be E; X¹⁸⁷ can be selected from an amino acid; andX¹⁸⁸ can be selected from D and E.

In IL-2Rγc ligands of Formula (12), X¹⁷¹ can be selected from H, K, andR; X¹⁷² can be selected from S, T, and Y; X¹⁷³ can be selected from D,E, F, I, L, M, V, W, and Y; X¹⁷⁴ can be V; X¹⁷⁵ can be selected from D,E, F, I, L, M, V, W, and Y; X¹⁷⁶ can be selected from D, E, H, N, Q, S,T, and Y; X¹⁷⁶ can be selected from E and Q; X¹⁷⁷ can be selected from Dand E; X¹⁷⁸ can be W; X¹⁷⁹ can be selected from D, E, and Q; X¹⁸⁰ can beG; X¹⁸¹ can be V; X¹⁸² can be E; X¹⁸³ can be L; X¹⁸⁴ can be W; X¹⁸⁵ canbe selected from F, I, L, M, V, W, and Y; X¹⁸⁶ can be E; X¹⁸⁷ can beselected from an amino acid; and X¹⁸⁸ can be selected from D and E.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 950 to SEQ ID NO: 1027:

SEQ ID NO: 950 I E C D T S Y G V Y I C W Q SEQ ID NO: 951I E C E E W R G V E L C W Q SEQ ID NO: 952P E G R E V V V C R D W Y G V E L C W Q SEQ ID NO: 953I W G R T V V E C Q D W E G V E L C W Q SEQ ID NO: 954L A L R K E V V C Q E Y Y G V E L C W I SEQ ID NO: 955H E A R E V V V C Q D W Y G V E L C W Q SEQ ID NO: 956M V N R E V V V C E D W Y G V E L C W Q SEQ ID NO: 957T A N Q T V V E C Q V W G G V E L C W Q SEQ ID NO: 958V E C Q E W G G V E L C W C SEQ ID NO: 959 D V E C V D W G G V E L C W HSEQ ID NO: 960 I V C E E W R G V E L C W L SEQ ID NO: 961D F E R S Y V V C Q D W D G V E L C W I SEQ ID NO: 962A H S R Q E V V C E E W Y G V E L C W I SEQ ID NO: 963S A P E R W V E C E D W Q G V E L C W V SEQ ID NO: 964Y S R E L Y V Q C E D W E G V E L C W I SEQ ID NO: 965V V C Q D W E G V E L C W Q SEQ ID NO: 966 D V V C Q N W E G V D L C W HSEQ ID NO: 967 S A G R Q E V V C Q D W N G V E L C W I SEQ ID NO: 968G Q G R E V V V C H D W Y G V E L C W Q SEQ ID NO: 969D W R R S V V E C Q D W Y G V E L C W Q SEQ ID NO: 970D V V C Q N W D G V D L C W H SEQ ID NO: 971T L G R T V V E C Q D W G G V E L C W Q SEQ ID NO: 972R L L N S V V E C L D W E G V E L C W Q SEQ ID NO: 973I V C E D W R G V E L C W I SEQ ID NO: 974 V V C Q E W E G V E L C W CSEQ ID NO: 975 G D R P K E V V C E D W K G V E L C W I SEQ ID NO: 976E R P R S F I E C Q E W E G V E L C W L SEQ ID NO: 977E G S T T T I E C E E W A G V E L C W L SEQ ID NO: 978A N Q N T V V E C Q D W H G V E L C W Q SEQ ID NO: 979R S D D E V V V C Q E W E G V E L C W Q SEQ ID NO: 980I E C E E W A G V E L C W L SEQ ID NO: 981T W N M S E L E C Q D W N G V E I C W H SEQ ID NO: 982G N D D S Y I V C E E W K G V E L C W I SEQ ID NO: 983F A H H G V V E C Q E W Y G V E L C W Q SEQ ID NO: 984L N R S V W I E C E E Y E G V E L C W L SEQ ID NO: 985W S K K A E V V C E E W G G V E F C W I SEQ ID NO: 986R S N Q T V V E C Q D W E G V E L C W Q SEQ ID NO: 987V V C Q E W E G V E L C W Y A G E C M Q SEQ ID NO: 988I L C Q E F E G V E L C W L E E S L A E SEQ ID NO: 989K S Q V E C Q D W E G V E L C W V V S E SEQ ID NO: 990K I T V E C Q D W D G V E L C W P T W I SEQ ID NO: 991R P Q I E C Q E W Q G V E L C W T R E E SEQ ID NO: 992V S C Q E W D G V E L C W V D G D L A A SEQ ID NO: 993I M C Q E W D G V E L C W L E R D K A N SEQ ID NO: 994G L E I A C E D W Y G V E L C W L R R A SEQ ID NO: 995G Y G V L C Q E W Q G V E L C W P V Q R E A G V SEQ ID NO: 996P Y G V V C Q D W A G V E L C W V E N R SEQ ID NO: 997K L T V E C Q D W D G V E L C W V G V E SEQ ID NO: 998I N C Q T W N G V E L C W V D E G L Y Q SEQ ID NO: 999V V C Q E W E G V E L C W V E P P L L P SEQ ID NO: 1000R V Q V E C E D W N G V E L C W P V R V SEQ ID NO: 1001D R Q V V C E E W D G V E L C W I E E S SEQ ID NO: 1002K T T V A C Q D W G G V E L C W V E R V SEQ ID NO: 1003R P E V V C Q E W E G V E L C W I S P L SEQ ID NO: 1004R L G V E C Q E W E G V D L C W I S A F SEQ ID NO: 1005K P V V V C E E W Q G V E L C W L E I Q SEQ ID NO: 1006V V C E V F Q G V E L C W C E N E E F T SEQ ID NO: 1007T D E V S C Q E W E G V E L C W I E R Q SEQ ID NO: 1008P V E V R C Q E W E G V E L C W V V G I SEQ ID NO: 1009G P E V V C E E F N R V E L C W V E Y N SEQ ID NO: 1010K Y I V E C Q E W G G V E L C W P E M V SEQ ID NO: 1011V T C Q E Y E G V E L C W T V G C A Y S SEQ ID NO: 1012V V C Q E W E G V E L C W Q T G P G A H A SEQ ID NO: 1013I V C E E Y N G V E L C W V E T S V K P SEQ ID NO: 1014E Q Q V V C Q E W N G V E L C W I E A G SEQ ID NO: 1015Q L G V E C Q N W R G V E L C W V S E I SEQ ID NO: 1016T A E V V C Q E W D G V E L C W I E V L SEQ ID NO: 1017S P S I V C E E W A G V E L C W V D Y S SEQ ID NO: 1018A V C Q D W Y G V E L C W C M Q D I L D SEQ ID NO: 1019V E C E E W G G V E L C W L A D E V M W SEQ ID NO: 1020H S T V I C Q D W D G V E L C W I E N D SEQ ID NO: 1021K K I V V C Q D W G G V E L C W T E D D SEQ ID NO: 1022S V E V V C E E W H G V E L C W P V F I SEQ ID NO: 1023R W A V S C Q D W Q G I E L C W P E W D SEQ ID NO: 1024R T G V E C Q D W H G V E L C W P V W E SEQ ID NO: 1025G Y G V V C E D F R G V E L C W L E R K SEQ ID NO: 1026R T E V E C E D W E G V E L C W L SEQ ID NO: 1027I L C E E W Q G V E L C W L E G G G S

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 949 to SEQ ID NO: 1027, wherein the amino acidsequence can be terminated with amino acids -G-G-on the N-terminus, onthe C-terminus, or on both the N- and C-termini.

An IL-2Rγc ligand can comprise an amino acid sequence selected from anyone of SEQ ID NO: 949 to SEQ ID NO: 1027, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

IL-2Rγc ligands of SEQ ID NO: 949 to SEQ ID NO: 1027 exhibit a bindingaffinity (IC₅) to the IL-2Rγc subunit of less than 100 μM.

An IL-2Rγc ligand can comprise, for example, from 5 to 50 amino acids,from 5 to 40 amino acids, from 5 to 30 amino acids, from 5 to 30 aminoacids, from 6 to 25 amino acids, or from 7 to 20 amino acids.

An IL-2Rγc ligand can exhibit a binding affinity (IC₅₀) to the humanIL-2Rγc subunit, to a mammalian IL-2Rγc subunit, or to both the humanIL-2Rγc subunit and a mammalian IL-2Rγc subunit from 1 pM to 100 μM,from 10 pM to 10 μM, from 100 pM to 1 μM, from, 0.001 μM to 1 μM, orfrom 0.01 μM to 1 μM.

An IL-2Rγc ligand provided by the present disclosure can exhibit, forexample, a binding affinity (IC₅₀) to the human IL-2Rγc subunit from 0.1μM to 50 μM.

An IL-2Rγc ligand can exhibit a binding affinity (IC₅₀) to the humanIL-2Rγc subunit, to a mammalian IL-2Rγc subunit, or to both the humanIL-2Rγc subunit and a mammalian IL-2Rγc subunit of less than 100 μM,less than 10 μM, less than 1 μM, less than 0.1 μM, or less than 0.01 μM.

An IL-2Rγc ligand can exhibit a binding affinity (IC₅₀) to each of thehuman IL-2Rγc subunit and to the human IL-2Rγc subunit of less than 100μM, less than 10 μM, less than 1 μM, less than 0.1 μM, or less than 0.01μM.

An IL-2Rγc ligand can exhibit a binding affinity (IC₅₀) to each of thehuman IL-2Rγc subunit and to the human IL-2Rγc subunit from 1 pM to 100μM, from 10 pM to 10 μM, from 100 pM to 1 μM, from, 0.001 μM to 1 μM, orfrom 0.01 μM to 1 μM.

An IL-2Rγc ligand provided by the present disclosure can exhibit abinding affinity (IC₅) to the human IL-2Rα (CD25) subunit of greaterthan 100 μM, greater than 1 mM, greater than 10 mM, or greater than 100mM.

An IL-2Rγc ligand can exhibit a binding affinity (IC₅₀) to the humanIL-2Rγc subunit that is at least 10 times greater, at least 50 timesgreater, at least 100 time greater, at least 500 times greater, or atleast 1,000 times greater than the binding affinity (IC₅₀) of theIL-2Rγc ligand to the human IL-2Rα subunit.

Amino acid sequences having SEQ ID NO: 268 to SEQ ID NO: 376 areexcluded from the scope of the amino acid sequences according to thepresent invention. In a genus or sub-genus of amino acid sequences thatotherwise encompasses any one of SEQ ID NO: 268 to SEQ ID NO: 376, theamino acid sequence of SEQ ID NO: 268 to SEQ ID NO: 376 are not includedwithin the scope of the genus or sub-genus.

SEQ ID NO: 268 I S A G R W G D V G D L I P SEQ ID NO: 269G V Q S R W G D V G D L I P W SEQ ID NO: 270F P V P R W G D W G D L I E L SEQ ID NO: 271 R W G D V G D L I GSEQ ID NO: 272 R W G D V G D L I W SEQ ID NO: 273 R W G D V G D L I GSEQ ID NO: 274 R W G D V G D L I V SEQ ID NO: 275 R W G D V G D L V SSEQ ID NO: 276 R W G D V G D L V M SEQ ID NO: 277 R W G D V G D M V ESEQ ID NO: 278 R Y G E V G D L L P SEQ ID NO: 279 R W G D W G D L L PSEQ ID NO: 280 R W G D W G D L I P SEQ ID NO: 281 R W G D W G D L V ASEQ ID NO: 282 R W G D W G D L V E SEQ ID NO: 283 R W G D W G D L V WSEQ ID NO: 284 R W G D W G D L V G SEQ ID NO: 285 R W G D V G D L V PSEQ ID NO: 286 R W G D W G D M V V SEQ ID NO: 287 W S G P G I L G E Y MSEQ ID NO: 288 W D G P G L G E F F SEQ ID NO: 289 W S G P G I L G E F MSEQ ID NO: 290 W Y G P G I L G E Y M SEQ ID NO: 291 W E G P G L G E Y MSEQ ID NO: 292 W E G P G I L G E Y SEQ ID NO: 293I D C G V A T V G E L C SEQ ID NO: 294 I S C S E A G L G E L CSEQ ID NO: 295 I D C S Q A M L G E L C SEQ ID NO: 296I D C S E A W L G E L C SEQ ID NO: 297 I D C S E A A L G T L CSEQ ID NO: 298 L D C S I A A L G E L C SEQ ID NO: 299L D C S E A I L G Q L C SEQ ID NO: 300 L D C G E A I L G E L CSEQ ID NO: 301 L D C R D A V L G E L C SEQ ID NO: 302M D C S E R A L G E L C SEQ ID NO: 303 M D C S Q A G SEQ ID NO: 304M D C R E A A L G E L C SEQ ID NO: 305 M D C W E A A L G E L CSEQ ID NO: 306 M D C S E A L L G E L C SEQ ID NO: 307M D C Y D A R L G D L C SEQ ID NO: 308 M D S S Q A A L G E L CSEQ ID NO: 309 V D C S E A V L G Q L C SEQ ID NO: 310L D C S R A S L G E L C SEQ ID NO: 311 M D C S Q A G L G E L CSEQ ID NO: 312 I D C S E A G L G E L C SEQ ID NO: 313I D C S E A A L G E L C SEQ ID NO: 314 I N C S E A V I G Q L CSEQ ID NO: 315 I D C S N A V V G Q L C SEQ ID NO: 316I D C S A A G L G E L C SEQ ID NO: 317 L D C S N A G W G D L CSEQ ID NO: 318 L D C S E A V L G E L C SEQ ID NO: 319L D C H L A V L G E L C SEQ ID NO: 320 L D C S V A V L G E L CSEQ ID NO: 321 L D C S E A W L G H L C SEQ ID NO: 322M D C S Q A A L G D L C SEQ ID NO: 323 M D C S W A W L G D L CSEQ ID NO: 324 M D C S D A V L G D L C SEQ ID NO: 325M D C H E A A L G H L C SEQ ID NO: 326 M D C S Q A V L G E L CSEQ ID NO: 327 M D C S I R A L G E L C SEQ ID NO: 328T E C S E A G L W E L C SEQ ID NO: 329 T E C S E A G L W E L CSEQ ID NO: 330 M D C R W A A L G E L C SEQ ID NO: 331M D C S K A A L G E L C SEQ ID NO: 332 M D C S E A V L G E L CSEQ ID NO: 333 M D C S I R A L G E L C SEQ ID NO: 334V D C S E A V L G Q L C SEQ ID NO: 335 M D C S E R A L G E L CSEQ ID NO: 336 I D C G V A T V G E L C SEQ ID NO: 337I D C S E A A L G E L C SEQ ID NO: 338 I N C S E A V I G D L CSEQ ID NO: 339 I D C S Q A M L G E L C SEQ ID NO: 340I D C S E A V L G E L C SEQ ID NO: 341 I D C S A A G L G E L CSEQ ID NO: 342 I D C S E A A L G T L C SEQ ID NO: 343L D C S N A G V G D L C SEQ ID NO: 344 L D C S I A A L G E L CSEQ ID NO: 345 L D C S E A I L G Q L C SEQ ID NO: 346L D C H L A V L G E L C SEQ ID NO: 347 L D C S V A V L G E L CSEQ ID NO: 348 L D C R D A V SEQ ID NO: 349 M D C S E R A L G E L CSEQ ID NO: 350 M D C S Q A A L G D L C SEQ ID NO: 351M D C S V A V L G D L C SEQ ID NO: 352 M D C R E A A L G E L CSEQ ID NO: 353 M D C W E A A L G E L C SEQ ID NO: 354M D C H E A A L G H L C SEQ ID NO: 355 M D C S Q A V L G E L CSEQ ID NO: 356 M D C Y D A R L G D L C SEQ ID NO: 357M D S S Q A A L G E L C SEQ ID NO: 358 T E C S E A G L W E L CSEQ ID NO: 359 M D C S E A V L G E L C SEQ ID NO: 360I S C S E A G L G E L C SEQ ID NO: 361 M D C S Q A A L G D L CSEQ ID NO: 362 M D C S Q A G L G E L C SEQ ID NO: 363I S C S E A G L G E L C SEQ ID NO: 364 I D C S N A V V G Q L CSEQ ID NO: 365 L D C S E A V L G E L C SEQ ID NO: 366L D C G E A I L G E L C SEQ ID NO: 367 L D C S E A V L G H L CSEQ ID NO: 368 M D C S Q A G L C E L C SEQ ID NO: 369M D C S D A V L G D L C SEQ ID NO: 370 M D C S E A L L G E L CSEQ ID NO: 371 H C L D M G C T F P V W SEQ ID NO: 372A R S D Y G L G A 1 W P SEQ ID NO: 373 R A C R V M P C L P D LSEQ ID NO: 374 S G C G R E L G W C SEQ ID NO: 375 T Q E V Y Y S L LSEQ ID NO: 376 G T Q E A C F G L L

Solid tumors exhibit metabolic differences from normal tissues. Thegreater reliance of solid tumors on glycolytic metabolism, produces amore acidic tumor microenvironment. For example, the solid tumormicroenvironment can have a pH that is from 1 pH to 2 pH less than thatof most normal tissues. This pH differential can be exploited to enhancethe activity of therapeutic agents in solid tumors relative to activityin normal peripheral tissue.

Using suitable pH-selective screening methods, peptides can beidentified that have a greater binding affinity to IL-2 at lower pH anda weaker binding affinity at a neutral pH. IL-2 agonists and antagonistscan be constructed based on the identified pH-selective peptides. ThesepH-selective agonists and antagonists can exhibit an enhancedtherapeutic index reflecting increased cytoxicity targeting solid tumorsand with reduced toxicity to normal tissue.

Acidic-biased affinity selection has been used to identify receptorligands having increased affinity at pH<6.5 commensurate with a solidtumor microenvironment and having decreased affinity at neutral pH>7.0commensurate with that of normal tissue. These peptide ligands can serveas components to construct pH-targeted and pH-selective antagonists andagonists.

An IL-2Rβ ligand provided by the present disclosure can comprise apH-selective IL-2Rβ ligand.

A pH-selective IL-2Rβ ligand can comprise the amino acid sequence ofFormula (1) (SEQ ID NO: 1055), the amino acid sequence of Formula (1a)(SEQ ID NO: 1056), or the amino acid sequence of Formula (1b) (SEQ IDNO: 1057):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—  (1)

—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—  (1a)

—X¹—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—X¹²—  (1b)

-   -   wherein, X¹ can be selected from an amino acid comprising a        large hydrophobic side chain; X² can be selected from an amino        acid; X³ can be selected from an amino acid; X⁴ can be selected        from an amino acid; X⁵ can be selected from an amino acid; X⁶        can be selected from an amino acid; X⁷ can be selected from an        amino acid; X⁸ can be selected from an amino acid comprising a        polar-neutral or an acidic side chain; X⁹ can be selected from        an amino acid comprising a polar-neutral or an acidic side        chain; X¹⁰ can be selected from an amino acid; X¹¹ can be        selected from an amino acid; and X¹² can be selected from an        amino acid.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selectedfrom an amino acid comprising a large hydrophobic side chain; X² can beselected from an amino acid comprising an acidic side chain; X³ can beselected from an amino acid; X⁴ can be selected from an amino acid; X⁵can be selected from an amino acid comprising small hydrophobic sidechain; X⁶ can be selected from an amino acid comprising a polar-neutralor an acidic side chain; X⁷ can be selected from an amino acidcomprising a polar-neutral or a large hydrophobic side chain; X⁸ can beselected from an amino acid comprising a small hydrophobic side chain;X⁹ can be selected from an amino acid comprising a polar-neutral or anacidic side chain; X¹⁰ can be selected from an amino acid comprising alarge hydrophobic side chain; X¹⁰ can be selected from an amino acidcomprising an acidic side chain; and X² can be selected from an aminoacid comprising a large hydrophobic side chain.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selectedfrom I, L, M, V, F, W, and Y; X² can be selected from D and E; X³ can beselected from an amino acid; X⁴ can be selected from an amino acid; X⁵can be selected from A, G, P, S, and T; X⁶ can be selected from H, N, Q,S, T, Y, D, and E; X⁷ can be selected from H, N, Q, S, T, Y, I, L, M, V,F, W, and Y; X⁸ can be selected from A, G, P, S, and T; X⁹ can beselected from H, N, Q, S, T, Y, D, and E; X¹⁰ can be selected from I, L,M, V, F, W, and Y; X¹¹ can be selected from D and E; and X¹² can beselected from I, L, M, V, F, W, and Y.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selectedfrom I, L, M, V, F, W, and Y; X² can be selected from D and E; X³ can beselected from an amino acid; X⁴ can be selected from an amino acid; X⁵can be A; X⁶ can be selected from H, N, Q, S, T, Y, D, and E; X⁷ can beselected from H, N, Q, S, T, Y, I, L, M, V, F, W, and Y; X⁸ can be G; X⁹can be selected from H, N, Q, S, T, Y, D, and E; X¹⁰ can be selectedfrom I, L, M, V, F, W, and Y; X¹¹ can be selected from D and E; and X¹²can be selected from I, L, M, V, F, W, and Y.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selectedfrom L, I, F and V.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X² can be selectedfrom D and E.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X⁶ can be selectedfrom Q, E, and D;

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X⁷ can be selectedfrom V, L, and I.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X⁹ can be selectedfrom E, D, and Q.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X¹⁰ can be selectedfrom L, V, I, and Y.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X¹¹ can be selectedfrom D and E.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X¹² can be selectedfrom L, I, and F.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selectedfrom L, I, F, and V; X² can be selected from D and E; X⁶ can be selectedfrom Q, E, and D; X⁷ can be selected from V, L, and I; X⁹ can beselected from E, D, and Q; X¹⁰ can be selected from L, V, I, and Y; X¹¹can be selected from D and E; and X¹² can be selected from L, I, and F.

In pH-selective IL-2Rβ ligands of Formula (1)-(1b), X¹ can be selectedfrom F, I, M, and Y; X² can be selected from E, D, and R; X³ can beselected from and amino acid; X⁴ can be selected from an amino acid; X⁵can be A; X⁶ can be selected from A, P, and Q; X⁷ can be selected from Iand V; X⁸ can be G; X⁹ can be selected from E and Q; X¹⁰ can be selectedfrom I, L, and V; X¹¹ can be selected from E, D, and Q; and X¹² can beselected from I and L.

A pH-selective IL-2Rβ ligand can comprise an amino acid sequenceselected from any one of SEQ ID NO: 400 to SEQ ID NO: 577:

SEQ ID NO: 400 D H K T W S A D C R I A Q V G E L C Q L SEQ ID NO: 401R R I A Q C S K A Q V G E L C E L SEQ ID NO: 402G V K D G W E D c G I A Q V G E L C V L SEQ ID NO: 403E D C W M A Q V G Q L C D L SEQ ID NO: 404R T L E H V E P C R I A G L G E L C D L SEQ ID NO: 405E Y C Q M A Q L G D L C D L SEQ ID NO: 406H G T F A C S L A Q V G D L C E L F G N SEQ ID NO: 407F D C R F A Q L G G L C D L SEQ ID NO: 408A K F F D C S F A P V G Y L C D L I V I SEQ ID NO: 409F E C R I A K V G E L C D L SEQ ID NO: 410F E C R T A P V G E L C D L W P W E L D SEQ ID NO: 411F E C W I A Q V G E L C D L SEQ ID NO: 412 F E C W R A Q V G E L C D LSEQ ID NO: 413 G D C R F A H L G D L C D L S G T S G A SEQ ID NO: 414F V V N E L G D C R F A Q L G E L C D L SEQ ID NO: 415G D C R I A E V G E L C D L SEQ ID NO: 416H D C W F A K L G E L C D L R Q M S F V SEQ ID NO: 417H D C Y S A H V G E L C D L N E P D G K SEQ ID NO: 418H E C R F A Q V G E L C D L SEQ ID NO: 419H Q C R F A H V G E L C D L F V F E S Y SEQ ID NO: 420I D C R F A R L G Y L C D L Q T N E H M SEQ ID NO: 421K A C S I A Q V G D L C E I Y G F D D A SEQ ID NO: 422R Q S R M W K A C S L A H L G E L C D L SEQ ID NO: 423K D C R L A Y V G E L C D L N R S D T I SEQ ID NO: 424A T F K D C R S S D V G E L C D M T N M SEQ ID NO: 425K D C R T A L I G D L C D L T L H L G G SEQ ID NO: 426K D C S I A Q V G E L C E F S R S G R T SEQ ID NO: 427Q D G A K L K E C R V A Q V G E L C E F SEQ ID NO: 428Q V L K N C R L A H I G E L C Y L S E R SEQ ID NO: 429R T M K Q C S I A Q V G E L C D L A V T SEQ ID NO: 430K S C A R A Q V G E L C Y I E G A E D A SEQ ID NO: 431M N Q K Y C K L A Q V G E L C D L S M D SEQ ID NO: 432L A C R A A Q V G Q L C D L SEQ ID NO: 433 L A C R M A Q V G E L C D LSEQ ID NO: 434 L A C W M A H V G Q L C E L E A H K V V SEQ ID NO: 435L D C R F A L L G Q L C D L F F G Q R P SEQ ID NO: 436L D C R I A P L G E L C D M F I S A F N SEQ ID NO: 437L D C R M A Q V G D L C D L SEQ ID NO: 438S D V L D C R V A Q V G S L C E L Y E SEQ ID NO: 439L D C S K A D V G E L C D P W W S R L K SEQ ID NO: 440A W N P L V L D C S T S Q V G D L C E L SEQ ID NO: 441F S G P D W L E C R F A Q L G Q M C D L SEQ ID NO: 442L E C R L A H L G E L C D L SEQ ID NO: 443 L E C R L A R L G D L C Y LSEQ ID NO: 444 L I M L E C R M A K L G E Y C Y F D A E SEQ ID NO: 445L E C R M A L V G D L C D L SEQ ID NO: 446 L E C R S A Q M G D L C D LSEQ ID NO: 447 L K C R M A R L G D L C D L D I G R N M SEQ ID NO: 448L L C R M A H L G E L C D L SEQ ID NO: 449L L C R N A Q V G Q I C D L M P F M L S SEQ ID NO: 450L L C S M A H V G E L C Y L L Q G T Q E SEQ ID NO: 451K E F L N C R I A Q V G E L C E M H Y E SEQ ID NO: 452A K S K G E L N C R Y A H V G E L C E L SEQ ID NO: 453 L Q C R LSEQ ID NO: 454 L R C R M SEQ ID NO: 455 L S C R M A L V G Q L C E LSEQ ID NO: 456 L S C S I A Q V G E L C D L SEQ ID NO: 457L S C W V A H L G D L C D L E R D V K E SEQ ID NO: 458N D C R F A H L G E L C D L D L E R A R SEQ ID NO: 459A S G N D C R M A Q V G Q L C D L E W M SEQ ID NO: 460S W V N N C R M A Q V G E L C D L P N W SEQ ID NO: 461T Y A K L V N Y C W T A Q L G E L C Y L SEQ ID NO: 462P D C S V A V L G E L C D L SEQ ID NO: 463G L N P M I P G C Q M A Q V G E L C E L SEQ ID NO: 464P Q C R T A L L G E L C E L SEQ ID NO: 465 P Q C R T A Q V G E L C D LSEQ ID NO: 466 K A G Q A C R I A H V G E L C D L N E T SEQ ID NO: 467Q A C R M A Q V G E L C D F Y G T P E S SEQ ID NO: 468L E F M W I Q D C G M A E V G E L C E L SEQ ID NO: 469Q D C K F A Q L W D L C D L SEQ ID NO: 470D E M Q D C Q I A Q V G E L C D L G L E SEQ ID NO: 471E Y F S H D Q D C Q T A Q L G E L C K M SEQ ID NO: 472Q D C R F A Q L G D L C D L SEQ ID NO: 473Q D C R F A H L G E L C D L T E G Q W W SEQ ID NO: 474Q D C R F A H V G D I C D L SEQ ID NO: 475G I P Q D C R I A L V G E L C D L D I A SEQ ID NO: 476Q D C R K A N V G E L C Y L D W D S P T SEQ ID NO: 477Q D C R L A H L G D L C D L W S P R Q N SEQ ID NO: 478R V F Q D C R L A L V G E L C E L V G P SEQ ID NO: 479S R S I R V Q D C R L A R V G D L C E L SEQ ID NO: 480Q D C R M A H L G E L C T L SEQ ID NO: 481 Q D C R M A Q V G H L C D LSEQ ID NO: 482 Q D C R M A Q V G E L C E L R G G D S S SEQ ID NO: 483S Y L Q D C R M A Q V G Q L C D L N D S SEQ ID NO: 484N Q F Q D C R R A L V G Q L C D M Y S K SEQ ID NO: 485A V K R F R Q D C R T A P V G T L C D L SEQ ID NO: 486Q D C R T A P V G D L C D I M G E D V L SEQ ID NO: 487W T W Q D C S L A Q V G D L C D I G K K SEQ ID NO: 488Q D C W M A Q L G E L C D L F S D H K V SEQ ID NO: 489P G V Q D C X I A H X G E L C E F V W N SEQ ID NO: 490S W G E L L Q E C R F A H L G E L C S L SEQ ID NO: 491W G R Q E C R F A N V G D L C D V S N Y SEQ ID NO: 492A V N Q E C R F A R L G E L C V L K N I SEQ ID NO: 493N Q V Q E C R I A Q L G D L C E M Y Q S SEQ ID NO: 494V L E V L R Q E C R M A Q V G E L C D L SEQ ID NO: 495S V W Q E C S M A Q V G D L C E L H I G SEQ ID NO: 496K I R R D S Q G C E I A Q V G E L C E L SEQ ID NO: 497Q G C W M A Q L G E L C D L S V Q E Y L SEQ ID NO: 498Q I C Q T A L V G E L C D L I A D V V T SEQ ID NO: 499W P M S Q F Q K C A T A Q V G E L C E L SEQ ID NO: 500F I A Q K C R L A K V G E L C D L G Y S SEQ ID NO: 501N L R Q N C R D A P V G E L C D L E W I SEQ ID NO: 502Q N C R F A Q L G Q L C D L SEQ ID NO: 503Q N C S T A K V G E L C D L L M E G T E SEQ ID NO: 504Q P C R M A H L F E L C D L SEQ ID NO: 505Q P C R N A H L G Q L C D L Q T W T N S SEQ ID NO: 506G Y E P I M R A C R N A Q V G D L C D L SEQ ID NO: 507V T G W T Y R D C R I A N V G D L C E L SEQ ID NO: 508Y Q K G Y S R E C S T A Q L G E L C D L SEQ ID NO: 509G A K G R L R E C Y M A Q V G E L C D L SEQ ID NO: 510R G C E T A Q V G E L C D E D M W H D R SEQ ID NO: 511S D C R I A R V G E L C D L L S D E G K SEQ ID NO: 512S D C R L A Q V G Q L C D R R R F R G V SEQ ID NO: 513L Y V V R N S D C R M A N V G E L C D L SEQ ID NO: 514E K S S D C R N A Q V G E L C D L SEQ ID NO: 515S D C S V A N V G D L C N L SEQ ID NO: 516N R L S F S S E C R L A Q V G E L C D L SEQ ID NO: 517S G C R F A H L G E L C D L SEQ ID NO: 518 T D C R M A Q V G E L C Y LSEQ ID NO: 519 T N C R L A H V G D L C D L SEQ ID NO: 520W Q R G Q G T Q C R F A L V G E L C D L SEQ ID NO: 521L K K Y R H V A C R M A V V G E L C D L SEQ ID NO: 522P M G M D P V A C R T A Q V G Q L C D L SEQ ID NO: 523V D C R Q A Q V G D L C E L S D E E I S SEQ ID NO: 524V D C W I A Q L G E L C E L E D G R R Q SEQ ID NO: 525M W I G H A V E C R F A H V G D L C D L SEQ ID NO: 526V L C R I A Q V G Q L C E L SEQ ID NO: 527 V M C R T A Q V G E L C D ISEQ ID NO: 528 V N C R Q A Q V G D L C D F E G I M S D SEQ ID NO: 529V N C S I A K L G E L C Y V SEQ ID NO: 530 W E C R W A Q V G D L C D LSEQ ID NO: 531 W Q C R W A Q V G E L C D L S S E N D N SEQ ID NO: 532W Y C W M A Q I G E L C D L SEQ ID NO: 533 Y Q C S I A R L G E L C D LSEQ ID NO: 534 Y A C R F A H V G D L C D L SEQ ID NO: 535E Q T R S G Y A C R T A Q V G E L C D L SEQ ID NO: 536Y D C Q K A Q L G E L C D L R Y S V R D SEQ ID NO: 537Y D C E M A Q V G E L C D L SEQ ID NO: 538D S Q Y K Y Y D C G R A Q L G E L C E L SEQ ID NO: 539Y D C R F A H L G D L C D L SEQ ID NO: 540 Y D C R F A H L G D L C D LSEQ ID NO: 541 Y D C R F A H L G D L C D L SEQ ID NO: 542Y D C R F A Q V G Q L C D I SEQ ID NO: 543 Y D C R I A Q V G Q L C D LSEQ ID NO: 544 Y D C R I A Q V G E L C D L SEQ ID NO: 545Y D C R I A Q V G D L C D L I S N S N R SEQ ID NO: 546M N D Y D C R I A R M G E L C D L L L D SEQ ID NO: 547Y D C R L A R L G D L C D L R V L G V E SEQ ID NO: 548Y D C R M A K V G D L C D L W S V W G R SEQ ID NO: 549I S Q H R N Y D C R M A Q L G E L C D L SEQ ID NO: 550Y D C R S A P V G E L C D L V P K D W A SEQ ID NO: 551T W A Y D C R T A E V G E L C D L P V Q SEQ ID NO: 552T I I Y D C R T A Q L G E L C E I N Y D SEQ ID NO: 553Y D C R V A H V G E L C D L P F V G R A SEQ ID NO: 554L S V Y D C S K A R L G E L C D L V L E SEQ ID NO: 555D G Y D Y W Y D C T M A Y V G E L C D F SEQ ID NO: 556T G K Y D C W K A M V G E L C D L R V M SEQ ID NO: 557M K Y Y E C R F A P L G E L C E L G V I SEQ ID NO: 558Y E C R I A Q V G E L C D L SEQ ID NO: 559N H W Y E C R I A Q V G E V C D L SEQ ID NO: 560Y E C R L A H V G D L C D L SEQ ID NO: 561 Y E C R M A N V G E L C D ISEQ ID NO: 562 Y E C R N A Q V G D L C D L G S Y V G N SEQ ID NO: 563V E E Y F C R I A H L G E L C D L G L K SEQ ID NO: 564T S S Y F C R M A E L F H L C D L E E S SEQ ID NO: 565K G G Y G C R F A R L G E L C D L D S T SEQ ID NO: 566Y L C Q V A G V G E L C D L E E S G R N SEQ ID NO: 567F E E Y N C R F A R L G E L C D M G S Q SEQ ID NO: 568G R F Y P C N M A Q V G E L C E L M E Y SEQ ID NO: 569Y P C R M A D V G E L C D L SEQ ID NO: 570L L S Y P C R M A Q V G E L C D I A M K SEQ ID NO: 571Y Q C R F A L V G Q L C D L SEQ ID NO: 572 Y Q C R L A H L G E L C D LSEQ ID NO: 573 Y Q C R M A Q V G E L C D L SEQ ID NO: 574G I D E D W Y S C W I A E V G E L C D L SEQ ID NO: 575Y W C R M A P V G E L C D L P G T V L SEQ ID NO: 576Y W C S V A K V G E L C D L SEQ ID NO: 577H G L Y Y C R T A H L G E L C D L Q S I

pH-selective IL-2Rβ ligands that exhibit a greater than 15% decrease inbinding to the IL-2Rβ receptor at pH 7.5 compared to pH 6.0 include SEQID NOS: 400, 402-405, 407, 409, 410, 411, 413, 415, 416, 418, 419, 420,421, 423, 425-432, 436, 438-440, 442-446, 448, 450, 452, 453-456,459-461, 463-468, 470, 471, 473-477, 479, 481-486, 489, 491, 493-496,498-507, 510-519, 521-524, 526-531, 534-537, 543, 545-548, 550, 551,558-564, 566, 568-573, and 575, where the pH-selective binding isdetermined as described in Examples 9-12.

pH-selective IL-2Rβ ligands that exhibit a greater than 50% decrease inbinding to the IL-2Rβ receptor at pH 7.5 compared to pH 6.0 include SEQID NOS: 400, 404-405, 407, 409, 410, 413, 415, 420, 426, 431, 432,438-440, 442, 444-446, 450, 452, 453, 455, 459, 464-467, 473-475, 479,480, 482-484, 486, 489, 493, 496, 498, 502, 504, 510-514, 516-519,521-523, 527-530, 537, 543, 545-547, 550, 558-564, 571-573, and 575,where the pH-selective binding is determined as described in Examples9-12.

A pH-selective pH-selective IL-2Rβ ligand can exhibit a greater than 99%decrease in binding to the IL-2Rβ receptor at pH 7.5 compared to pH 6.0,a greater than 90%, a greater than 80%, a greater than 70%, a greaterthan 60%, a greater than 50%, a greater than 40%, a greater than 30%, agreater than 20%, or a greater than 10% decrease in binding to theIL-2Rβ receptor at pH 7.5 compared to pH 6.0, where the pH-selectivebinding is determined as described in Examples 9-12.

A pH-selective pH-selective IL-2Rβ ligand can comprise from 5 to 30amino acids.

A pH-selective pH-selective IL-2Rβ ligand can exhibit a binding affinityto the human IL-2Rβ subunit at pH 6.0 from 1 pM to 100 μM.

A pH-selective pH-selective IL-2Rβ ligand can exhibit a binding affinityto the human IL-2Rβ subunit at pH 6.0 from 0.1 μM to 50 μM.

A pH-selective pH-selective IL-2Rβ ligand can exhibit a binding affinityto the human IL-2Rβ subunit at pH 6.0 of less than 100 μM.

A pH-selective pH-selective IL-2Rβ ligand can exhibit a binding affinityto a mammalian IL-2Rβ subunit at pH 6.0 of less than 100 μM.

A pH-selective pH-selective IL-2Rβ ligand can exhibit a binding affinityto each of the human IL-2Rβ subunit and to the human IL-2Rγc subunit ofless than 100 μM.

A pH-selective pH-selective IL-2Rβ ligand can exhibit a binding affinityto the human IL-2Rα (CD25) subunit of greater than 100 μM.

A pH-selective pH-selective IL-2Rβ ligand can exhibit a binding affinityto the human IL-2Rβ subunit that is at least 10 times greater than thebinding affinity of the IL-2Rβ ligand to the human IL-2Rα subunit.

Using suitable pH-selective screening methods, peptides can beidentified that have a greater binding affinity to IL-2 at lower pH anda weaker binding affinity at a neutral pH. IL-2 agonists and antagonistscan be constructed based on the identified pH-selective peptides. ThesepH-selective agonists and antagonists can exhibit an enhancedtherapeutic index reflecting increased cytotoxicity targeting solidtumors and with reduced toxicity to normal tissue.

Acidic-biased affinity selection has been used to identify receptorligands having increased affinity at pH<6.5 commensurate with a solidtumor microenvironment and having decreased affinity at neutral pH >7.0commensurate with that of normal tissue. These peptide ligands can serveas components to construct pH-targeted and pH-selective antagonists andagonists.

Certain IL-2Rβ ligands provided by the present disclosure exhibit abinding affinity to the IL-2Rβ subunit of less than 10 μM, and a bindingaffinity (IC₅₀) to the IL-2Rγc subunit of greater than 100 μM.

Certain families of IL-2Rβ ligands bind to the IL-2Rβ subunitcompetitively with certain other families of IL-2Rβ ligands andnon-competitively with other families of IL-2Rβ ligands and alsonon-competitively with IL-2, and withnd no detectable binding to the theIL-2Rγc subunit.

A specific binding site of the IL-2Rβ subunit can be defined as abinding site in which certain IL-2Rβ ligands of the group of IL-2Rβligands having amino acid sequences of SEQ ID NOS: 1-163, 164-182,578-808, 1028-1043, 1052-1060, and 1084, competitively bind to thebinding site with each of the other IL-2Rβ ligands within the group ofIL-2Rβ ligands; an IL-2Rβ ligand having amino acid sequence of SEQ IDNO: 1044 does not compete for binding to the binding site with the groupof IL-2Rβ ligands; and IL-2 does not compete for binding to the bindingsite with the group of IL-2Rβ ligands.

Certain IL-2Rβ ligands of the group of IL-2Rβ ligands (SEQ ID NOS:1-163, 164-182, 578-808, 1028-1043, 1052-1060, and 1084) have a bindingaffinity (IC₅₀) to the IL-2Rβ subunit of less than 100 μM and a bindingaffinity (IC₅₀) to the IL-2Rγc no detectable binding.

An IL-2Rγc ligand having the amino acid sequence of SEQ ID NO: 224 doesnot compete for binding to the binding site with the group of IL-2Rβligands.

The group of IL-2Rβ ligands (SEQ ID NOS: 1-163, 164-182, 578-808,1028-1043, 1052-1060, and 1084) can comprise the group of IL-2Rβ ligandshaving the amino acid sequence of SEQ ID NOS: 58, 83, 142, 169, 170,1033, and 663.

This IL-2R binding site for IL-2Rβ ligands can be characterized usingcompetitive binding assays as described, for example, in Example 20.

Certain IL-2Rγc ligands provided by the present disclosure exhibit abinding affinity to the IL-2Rγc subunit of less than 100 μM, and abinding affinity (IC₅₀) to the IL-2Rβ subunit of greater than 100 μM.

Certain families of IL-2Rγc ligands bind to the IL-2Rγc subunitcompetitively with certain other families of IL-2Rγc ligands andnon-competitively with other families of IL-2Rγc ligands.

A specific binding site of the IL-2Rγc subunit can be defined as abinding site in which the group of IL-2Rγc ligands having amino acidsequences of SEQ ID NOS: 194-210, 904-913, 211-233, 914-920, 234-245,246-254, 921-922, 265-267, 932-940, 1051, and 1065-1082, competitivelybind to the binding site with each of the other IL-2Rγc ligands withinthe group of IL-2Rγc ligands; an IL-2Rγc ligand having amino acidsequence of SEQ ID NO: 948 does not compete for binding to the bindingsite with the group of IL-2Rγc ligands.

Certain IL-2Rγc ligands of the group of IL-2Rγc ligands (SEQ ID NOS:194-210, 904-913, 211-233, 914-920, 234-245, 246-254, 921-922, 265-267,932-940, 1051, and 1065-1082) have a binding affinity (IC₅₀) to theIL-2Rγc subunit of less than 100 μM and a binding affinity (IC₅₀) to theIL-2Rβ subunit of greater than 100 μM.

An IL-2Rβ ligand having the amino acid sequence of SEQ ID NO: 58 doesnot compete for binding to the binding site with the group of IL-2Rγcligands.

The group of IL-2Rγc ligands can comprise the group of IL-2Rγc ligandshaving the amino acid sequence of SEQ ID NOS: 198, 202, 224, 236, 248,1051, and 266.

This IL-2R binding site for these IL-2Rγc ligands can be characterizedusing competitive binding assays as described, for example, in Example20.

Compounds provided by the present disclosure comprising an IL-2Rβ ligandhaving an amino acid sequence of SEQ ID NOS: 1-163, 164-182, 578-808,1028-1043, 1052-1060 or 1084 can bind to the specific binding site onthe IL-2Rβ subunit; and Compounds provided by the present disclosurecomprising an IL-2Rγc ligand having an amino acid sequence of SEQ IDNOS: 194-210, 904-913, 211-233, 914-920, 234-245, 246-254, 921-922,265-267, 932-940, 1051, or 1065-1082, can bind to the specific bindingsite on the IL-2Rγc subunit.

Methods of treating a disease in a patient provided by the presentdisclosure can comprise administering to a patient a therapeuticallyeffective amount of a compound comprising an IL-2Rβ ligand having anamino acid sequence of SEQ ID NOS: 1-163, 164-182, 578-808, 1028-1043,1052-1060 or 1084 and/or an IL-2Rγc ligand having an amino acid sequenceof SEQ ID NOS: 194-210, 904-913, 211-233, 914-920, 234-245, 246-254,921-922, 265-267, 932-940, 1051, or 1065-1082.

Methods of treating a disease in a patient provided by the presentdisclosure can comprise administering to a patient a therapeuticallyeffective amount of a compound that binds to the specific binding siteof the IL-2Rβ and/or the specific binding site of the IL-2Rγc subunit.

Methods provided by the present disclosure include methods of modulatingthe activity of IL-2R by providing a ligand or compound that interactswith the specific binding site of the IL-2Rβ and/or the specific bindingsite of the IL-2Rγc subunit.

Methods of diagnosing a disease in a patient provided by the presentdisclosure comprise administering to a patient an effective amount of aligand or a compound that binds to the specific binding site of theIL-2Rβ and/or the specific binding site of the IL-2Rγc subunit.

Peptides provided by the present disclosure can be synthesized bymethods known in the art, for example, by using standard solid phasetechniques. The standard methods include exclusive solid phasesynthesis, partial solid phase synthesis methods, fragment condensation,classical solution synthesis, and even by recombinant DNA technology. Onsolid phase, the synthesis can commence from the C-terminal end of thepeptide using an α-amino protected resin. A suitable starting materialcan be prepared, for example, by attaching the required α-amino acid toa chloromethylated resin, a hydroxymethyl resin, or a benzhydrylamineresin. Peptides provided by the present disclosure can be prepared bycoupling an α-amino-protected amino acid to the chloromethylated resinwith the aid of, for example, a cesium bicarbonate catalyst. After theinitial coupling, the α-amino protecting group can be removed by achoice of reagents including trifluoroacetic acid (TFA) or hydrochloricacid (HCl) solutions in organic solvents at room temperature.

The α-amino protecting groups are those known to be useful in the art ofstepwise synthesis of peptides. Included are acyl type protecting groupssuch as formyl, trifluoroacetyl, and acetyl, aromatic urethane typeprotecting groups such as benzyloxycarboyl (Cbz) and substituted Cbz,aliphatic urethane protecting groups such as tert-butyloxycarbonyl(Boc), isopropyloxycarbonyl, and cyclohexyloxycarbonyl and alkyl typeprotecting groups such as benzyl and triphenylmethyl. Boc and Fmoc arepreferred protecting groups. The side chain protecting group remainsintact during coupling and is not split off during the deprotection ofthe amino-terminus protecting group or during coupling. The side chainprotecting group must be removable upon the completion of the synthesisof the final peptide and under reaction conditions that will not alterthe target peptide.

Suitable side chain protecting groups for Tyr include tetrahydropyranyl,tert-butyl, trityl, benzyl, Cbz, Z—Br—Cbz, and 2,5-dichlorobenzyl.Suitable side chain protecting groups for Asp include benzyl,2,6-dichlorobenzyl, methyl, ethyl, and cyclohexyl. Suitable side chainprotecting groups for Thr and Ser include acetyl, benzoyl, trityl,tetrahydropyranyl, benzyl, 2,6-dichlorobenzyl, and Cbz. The side chainprotecting group for Thr and Ser is benzyl. Suitable side chainprotecting groups for Arg include nitro, tosyl (Tos), Cbz,adamantyloxycarbonyl mesitoylsulfonyl (Mts), or Boc. Suitable side chainprotecting groups for Lys include Cbz, 2-chlorobenzyloxycarbonyl(2-ClCbz), 2-bromobenzyloxycarbonyl (2-BrCbz), Tos, or Boc.

After removal of the α-amino protecting group, the remaining protectedamino acids can be coupled stepwise in a desired order. An excess ofeach protected amino acid is generally used with an appropriate carboxylgroup activator such as dicyclohexylcarbodiimide (DCC) in solution, forexample, in methylene chloride (CH₂ Cl₂), dimethyl formamide (DMF)mixtures.

After the desired amino acid sequence has been completed, the desiredpeptide can be decoupled from the resin support by treatment with areagent such as trifluoroacetic acid or hydrogen fluoride (HF), whichnot only cleaves the peptide from the resin, but also cleaves allremaining side chain protecting groups. When the chloromethylated resinis used, hydrogen fluoride treatment results in the formation of thefree peptide acids. When the benzhydrylamine resin is used, hydrogenfluoride treatment results directly in the free peptide amide.Alternatively, when the chloromethylated resin is employed, the sidechain protected peptide can be decoupled by treatment of the peptideresin with ammonia to give the desired side chain protected amide orwith an alkylamine to give a side chain protected alkylamide ordialkylamide. Side chain protection is then removed in the usual fashionby treatment with hydrogen fluoride to give the free amides,alkylamides, or dialkylamides. These solid phase peptide synthesisprocedures are well known in the art and can be used to not onlydetermine the minimum size of a peptide with such activity, one can alsomake all of the peptides that form the group of peptides that differfrom the preferred motif (or the minimum size of that motif) in one,two, or more residues. Individual peptides can then be screened forability to bind to the IL-2Rβ subunit and/or to the IL-2Rγc subunit.Peptide synthesis methods can also be used to synthesize truncationanalogs and deletion analogs and combination of truncation and deletionanalogs of all of the peptide compounds provided by the presentdisclosure.

These procedures can also be used to synthesize peptides in which aminoacids other than the 20 naturally occurring, genetically encoded, aminoacids are substituted at one, two, or more positions of any of thecompounds of the invention. For example, naphthylalanine can besubstituted for tryptophan, facilitating synthesis. Other syntheticamino acids that can be substituted into the peptides of the presentinvention include L-hydroxypropyl, L-3, 4-dihydroxyphenylalanyl, d aminoacids such as L-d-hydroxylysyl and D-d-methylalanyl, L-a-methylalanyl, bamino acids, and isoquinolyl. D-amino acids and non-naturally occurringsynthetic amino acids can also be incorporated into peptides provided bythe present disclosure.

A naturally occurring side chains of the 20 genetically encoded aminoacids (or D amino acids) can be replaced with other side chains, forinstance with groups such as alkyl, lower alkyl, cyclic 4-, 5-, 6-, to7-membered alkyl, amide, amide lower alkyl, amide di(lower alkyl), loweralkoxy, hydroxy, carboxy and the lower ester derivatives thereof, andwith 4-, 5-, 6-, to 7-membered heterocyclic. For example, prolineanalogs in which the ring size of the proline residue is changed from 5members to 4, 6, or 7 members can be employed. Cyclic groups can besaturated or unsaturated, and if unsaturated, can be aromatic ornon-aromatic.

Cyclic groups can be saturated or unsaturated, and if unsaturated, canbe aromatic or non-aromatic. Heterocyclic groups can contain, forexample, one or more nitrogen, oxygen, and/or sulfur heteroatoms.Examples of such groups include the furazanyl, furyl, imidazolidinyl,imidazolyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl (e.g.,morpholino), oxazolyl, piperazinyl (e.g., 1-piperazinyl), piperidyl(e.g., 1-piperidyl, and piperidino), pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl(e.g., 1-pyrrolidinyl), pyrrolinyl, pyrrolyl, thiadiazolyl, thiazolyl,thienyl, thiomorpholinyl (e.g., thiomorpholino), and triazolyl. Theseheterocyclic groups can be substituted or unsubstituted. Where a groupis substituted, the substituent can be alkyl, alkoxy, halogen, oxygen,or substituted or unsubstituted phenyl.

A peptide provided by the present disclosure can be modified, forexample, by phosphorylation, and by other methods known in the art.Thus, the peptides of the disclosure can also serve as a basis toprepare peptide mimetics with similar biological activity.

A variety of techniques are available for constructing peptide mimeticswith the same or similar desired biological activity as a correspondingpeptide but with more favorable activity than the peptide with respectto solubility, stability, and susceptibility to hydrolysis andproteolysis. The following describes methods for preparing peptidemimetics modified at the N-terminal amino group, the C-terminal carboxylgroup, and/or changing one or more of the amido linkages in the peptideto a non-amido linkage. Two or more such modifications can be coupled inone peptide mimetic structure (e.g., modification at the C-terminalcarboxyl group and inclusion of a —CH₂-carbamate linkage between twoamino acids in the peptide).

Peptides can be synthesized as the free or can be prepared as thecorresponding amide or ester. The amino and/or carboxy terminus of thepeptide can also be modified. Amino terminus modifications includemethylating (i.e., —NHCH₃ or —NH(CH₃)₂), acetylating, adding acarbobenzoyl group, or blocking the amino terminus with any blockinggroup containing a carboxylate functionality defined by RCOO—, where Rcan be selected from the group consisting of naphthyl, acridinyl,steroidyl, and similar groups. Carboxy terminus modifications includereplacing the free acid with a carboxamide group or forming a cycliclactam at the carboxy terminus to introduce structural constraints.Amino terminus modifications also include, for example, alkylating,acetylating, adding a carbobenzoyl group, and forming a succinimidegroup.

In preparing peptide mimetics in which the C-terminal carboxyl group isreplaced by an ester such as —C(O)OR, the resins used to prepare thepeptide acids are employed, and the side chain protected peptide iscleaved with base and the appropriate alcohol, such as methanol. Sidechain protecting groups can then be removed in the usual fashion bytreatment with hydrogen fluoride to obtain the desired ester.

In preparing peptide mimetics in which the C-terminal carboxyl group isreplaced by the amide —C(O)NR³R⁴, a benzhydrylamine resin is used as thesolid support for peptide synthesis. Upon completion of the synthesis,hydrogen fluoride treatment to release the peptide from the supportresults directly in the free peptide amide (i.e., the C-terminus is—C(O)NH₂). Alternatively, use of the chloromethylated resin duringpeptide synthesis coupled with reaction with ammonia to cleave the sidechain protected peptide from the support yields the free peptide amideand reaction with an alkylamine or a dialkylamine yields a side chainprotected alkylamide or dialkylamide (i.e., the C-terminus is —C(O)NRR¹where R and R¹ are as defined above). Side chain protection can then beremoved in the usual fashion by treatment with hydrogen fluoride to givethe free amides, alkylamides, or dialkylamides.

The C-terminal carboxyl group or a C-terminal ester can be induced tocyclize by internal displacement of the —OH or the ester (—OR) of thecarboxyl group or ester respectively with the N-terminal amino group toform a cyclic peptide. For example, after synthesis and cleavage to givethe peptide acid, the free acid is converted to an activated ester by anappropriate carboxyl group activator such as dicyclohexylcarbodiimide(DCC) in solution, for example, in methylene chloride (CH₂Cl₂), dimethylformamide (DMF) mixtures. The cyclic peptide can then be formed byinternal displacement of the activated ester with the N-terminal amine.

Peptides can be cyclized or can incorporate a desamino or descarboxyresidue at the termini of the peptide, so that there is no terminalamino or carboxyl group, to decrease susceptibility to proteases or torestrict the conformation of the peptide. C-terminal functional groupsof the peptides include, for example, amide, amide lower alkyl, amidedi(lower alkyl), lower alkoxy, hydroxy, and carboxy, and the lower esterderivatives thereof, and pharmaceutically acceptable salts thereof.

Peptide compounds provided by the present disclosure can also serve asstructural models for non-peptidic compounds with similar biologicalactivity. Those of skill in the art recognize that a variety oftechniques are available for constructing compounds with the same orsimilar desired biological activity as a particular peptide compound butwith more favorable activity than the peptide compound with respect to,for example, solubility, stability, and susceptibility to hydrolysis andproteolysis. These techniques include replacing the peptide backbonewith a backbone composed of phosphonates, amidates, carbamates,sulfonamides, secondary amines, and N-methylamino acids.

Peptide mimetics with one or more of the peptidyl linkages —C(O)NH— canbe replaced by linkages as a —CH₂-carbamate linkage, a phosphonatelinkage, a —CH₂-sulfonamide linkage, a urea linkage, a secondary amine(—CH₂NH—) linkage, or an alkylated peptidyl linkage —C(O)NR⁶— where R⁶is C₁₋₆ alkyl can be prepared during conventional peptide synthesis bysubstituting a suitably protected amino acid analogue for the amino acidreagent at the appropriate point during synthesis.

Suitable reagents include, for example, amino acid analogs in which thecarboxyl group of the amino acid has been replaced with a moietysuitable for forming one of the above linkages. For example, if a—C(O)NR— in the peptide can be replaced with a —CH₂-carbamate linkage(—CH₂OC(O)NR—), then the carboxyl (—COOH) group of a suitably protectedamino acid is first reduced to the —CH₂OH group which is then convertedby conventional methods to a —OC(O)Cl functionality or apara-nitrocarbonate —OC(O)O—C₆H₄-p-NO₂ functionality. Reaction of eitherof such functional groups with the free amine or an alkylated amine onthe N-terminus of the partially fabricated peptide found on the solidsupport leads to the formation of a —CH₂OC(O)NR— linkage. Similarly, anamido linkage in a peptide can be replaced with a phosphonate linkage.

Replacing an amido linkage in the peptide with a —CH₂-sulfonamidelinkage can be achieved by reducing the carboxyl (—COOH) group of asuitably protected amino acid to the —CH₂OH group and the hydroxyl groupis then converted to a suitable leaving group such as a tosyl group byconventional methods. Reaction of the tosylated derivative with, forexample, thioacetic acid followed by hydrolysis and oxidativechlorination will provide for the —CH₂—S(O)₂Cl functional group whichreplaces the carboxyl group of the otherwise suitably protected aminoacid. Use of this suitably protected amino acid analogs in peptidesynthesis provides for inclusion of an —CH₂S(O)₂NR— linkage, whichreplaces the amido linkage in the peptide thereby providing a peptidemimetic. Replacing an amido linkage in the peptide with a urea linkagecan be achieved using similar methods.

Secondary amine linkages in which a —CH₂NH—linkage replaces the amidolinkage in the peptide can be prepared by employing, for example, asuitably protected dipeptide analogue in which the carbonyl bond of theamido linkage has been reduced to a CH₂ group by conventional methods.For example, in the case of diglycine, reduction of the amide to theamine will yield after deprotection H₂NCH₂CH₂NHCH₂COOH which is thenused in N-protected form in the next coupling reaction. The preparationof such analogs by reduction of the carbonyl group of the amido linkagein the dipeptide is known in the art.

Suitably protected amino acid analogs can be employed in a conventionalpeptide synthesis in the same manner as would the corresponding aminoacid. For example, typically about 3 equivalents of the protected aminoacid analog can be employed in this reaction. An inert organic diluentsuch as methylene chloride or DMF is employed and, when an acid isgenerated as a reaction by-product, the reaction solvent will typicallycontain an excess amount of a tertiary amine to scavenge the acidgenerated during the reaction. One particularly preferred tertiary amineis diisopropylethylamine which is typically employed in about 10-foldexcess. The reaction results in incorporation into the peptide mimeticof an amino acid analogue having a non-peptidyl linkage. Suchsubstitution can be repeated as desired such that from zero to all ofthe amido bonds in the peptide have been replaced by non-amido bonds.

Peptides provided by the present disclosure can be cyclized or adesamino or descarboxy residue can be incorporated at the termini of thepeptide, so that there is no terminal amino or carboxyl group, todecrease susceptibility to proteases or to restrict the conformation ofthe peptide. C-terminal functional groups of the compounds of thepresent invention include amide, amide lower alkyl, amide di(loweralkyl), lower alkoxy, hydroxy, and carboxy, and the lower esterderivatives thereof, and the pharmaceutically acceptable salts thereof.

Peptides provided by the present disclosure can exist in a cyclized formwith an intramolecular disulfide bond between the thiol groups of thecysteines. Alternatively, an intermolecular disulfide bond between thethiol groups of the cysteines can be produced to yield a dimeric (orhigher oligomeric) compound. One or more of the cysteine residues mayalso be substituted with a homocysteine. One of the sulfurs can bereplaced by a CH₂ group or other isostere for sulfur. These analogs canbe made via an intramolecular or intermolecular displacement. One ofskill in the art will readily appreciate that this displacement can alsooccur using other homologs of the α-amino-g-butyric acid derivativeshown above and homocysteine.

Alternatively, the amino-terminus of the peptide can be capped with anα-substituted acetic acid, wherein the α-substituent is a leaving group,such as an α-haloacetic acid, for example, α-chloroacetic acid,α-bromoacetic acid, or α-iodoacetic acid. Peptides provided by thepresent disclosure can be cyclized or dimerized via displacement of theleaving group by the sulfur of the cysteine or homocysteine residue.

An IL-2R agonist and a compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand can be, for example, a synthetic peptide, a conjugate ofa peptide to another peptide or protein, a recombinant fusion protein,or a single chain peptide.

An IL-2R agonist compound can comprise an IL-2Rβ ligand provided by thepresent disclosure, an IL-2Rγc ligand provided by the presentdisclosure, or both an IL-2Rβ ligand provided by the present disclosureand an IL-2Rγc ligand provided by the present disclosure.

An IL-2R agonist compound can comprise an IL-2Rβ ligand provided by thepresent disclosure such as an IL-2Rβ ligand of SEQ ID NOS: 1-193,578-903, 1028-1050, 1052-1064, or 1084, an IL-2Rγc ligand provided bythe present disclosure such as an IL-2Rγc ligand of SEQ ID. NO: 194-267,904-1027, or 1065-1083, or both an IL-2Rβ ligand provided by the presentdisclosure and an IL-2Rγc ligand provided by the present disclosure.

A peptide provided by the present disclosure can comprise an IL-2Rβligand or an IL-2Rγc ligand and additional amino acids.

The additional amino acids can be bonded to the C-terminus of the IL-2Rβligand or the IL-2Rγc ligand, to the N-terminus of the IL-2Rβ ligand orthe IL-2Rγc ligand, or to both the C-terminus and the N-terminus of theIL-2Rβ ligand or the IL-2Rγc ligand.

A peptide comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand cancomprise, for example, from 10 to 50 amino acids, from 10 to 40 aminoacids, from 10 to 30 amino acids, or from 15 to 25 amino acids.

A peptide comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand cancomprise, for example, from 5 to 300 amino acids, from 10 to 200 aminoacids, or from 10 to 100 amino acids.

A peptide comprising an IL-2Rβ ligand and an IL-2Rγc ligand can have atleast substantially the same binding affinity (IC₅₀) for the respectivehuman IL-2 subunit as that of the respective IL-2R ligand alone.

A compound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand can be aconjugate.

A conjugate can comprise one or more IL-2Rβ ligands, one or more IL-2Rγcligands, or a combination thereof.

A conjugate can be a homodimer comprising two IL-2Rβ ligands or twoIL-2Rγc ligands.

A conjugate can be a heterodimer comprising at least one IL-2Rβ ligandand at least one IL-2Rγc ligand.

A conjugate can be a heterodimer comprising at least one IL-2Rβ ligandand at least one IL-2Rγc ligand covalently coupled to a protein.

A conjugate can comprise a linker, wherein the linker is configured toattach an IL-2Rβ ligand and/or an IL-2Rγc ligand to one or more otherIL-2Rβ ligands and/or IL-2Rγc ligands. The linker can be attached to anIL-2Rβ ligand and/or an IL-2Rγc ligand and any additional moiety by acovalent bond, or by non-covalent bonding such as by ionic bonding.

Each IL-2Rβ ligand and/or an IL-2Rγc ligand can independently beattached to a linker through the C-terminus, the N-terminus, or both theC-terminus and N-terminus.

For example, in a homodimer, the C-terminus of a first IL-2Rβ ligand andthe C-terminus of a second IL-2Rβ ligand can be attached to the linker;the N-terminus of a first IL-2Rβ ligand and the N-terminus of a secondIL-2Rβ ligand can be attached to the linker; or the C-terminus of afirst IL-2Rβ ligand and the N-terminus of a second IL-2Rβ ligand can beattached to the linker.

For example, in a homodimer, the C-terminus of a first IL-2Rγc ligandand the C-terminus of a second IL-2Rγc ligand can be attached to thelinker; the N-terminus of a first IL-2Rγc ligand and the N-terminus of asecond IL-2Rγc ligand can be attached to the linker; or the C-terminusof a first IL-2Rγc ligand and the N-terminus of a second IL-2Rγc ligandcan be attached to the linker.

For example, in a heterodimer, the C-terminus of an IL-2Rβ ligand andthe C-terminus of an IL-2Rγc ligand can be attached to the linker; theN-terminus of an IL-2Rβ ligand and the N-terminus of an IL-2Rγc ligandcan be attached to the linker; the C-terminus of an IL-2Rβ ligand andthe N-terminus of an IL-2Rγc ligand can be attached to the linker, orthe N-terminus of an IL-2Rβ ligand and the C-terminus of an IL-2Rγcligand can be attached to the linker.

A heterodimeric compound comprising an IL-2Rβ ligand and an IL-2Rγcligand can be configured to activate the IL-2 receptor.

A heterodimeric compound comprising an IL-2Rβ ligand and an IL-2Rγcligand can be configured to activate the IL-2 receptor withoutactivating cells expressing the IL-2Rα ligand.

For example, when incubated with a heterodimeric compound comprising anIL-2Rβ ligand and an IL-2Rγc ligand, primary human peripheral bloodmononuclear cells (PBMC) expressing the IL-2Rβγc subunits phosphorylatetranscription 5 (STAT5); and primary human peripheral blood mononuclearcells (PBMC) expressing the IL-2Rα (CD25) subunit, do not phosphorylatetranscription 5 (STAT5).

A heterodimer can comprise an IL-2Rβ ligand, an IL-2Rγc ligand, and alinker, wherein the linker is configured such that the heterodimer is anagonist for the IL-2 receptor.

A linker can comprise a length that facilitates binding of an IL-2Rβligand and/or an IL-2Rγc ligand to the IL-2 receptor. For example, alinker can have a length, for example, from 20 Å to 100 Å, from 30 Å to80 Å, or from 40 Å to 60 Å.

A linker can comprise a chemical structure that facilitates binding ofan IL-2Rβ ligand and/or an IL-2Rγc ligand to the IL-2 receptor. Forexample, a linker can comprise a peptide, or a hydrocarbon.

A peptide linker can comprise, for example, from 5 to 100 amino acids,from 5 to 80 amino acids, from 5 to 60 amino acids, from 5 to 40 aminoacids, from 5 to 20 amino acids, or from 5 to 10 amino acids. A peptidelinker can comprise, for example, from 2 to 100 amino acids, from 2 to80 amino acids, from 2 to 60 amino acids, from 2 to 40 amino acids, from2 to 20 amino acids, from 5 to 10 amino acids, or from 2 to 5 aminoacids.

A hydrocarbon linker can be a polyethylene oxide. A polyethylene oxidecan have the structure of the formula —(O—(CH₂)₂—)_(n)—(CH₂)₂—, where nis an integer from 1 to 30.

A hydrocarbon linker can be derived from a polyethylene oxide having thestructure of the formula H₂N—(O—(CH₂)₂—)_(n)—(CH₂)₂—COOH, where n is aninteger from 1 to 30.

Peptide dimer compounds can comprise two monomer subunits, wherein thepeptide dimer compounds comprise IL-2Rβ ligands and/or IL-2Rγc ligands.Monomer subunits present in a peptide dimer compound can be linked ateither their C- or N-terminus or via internal amino acid residues suchas by a linker moiety. Both monomer subunits can be linked via theirrespective N-termini, both monomer subunits can be linked via theirrespective C-termini, or both monomer subunits can be linked viainternal amino acid residues. One monomer subunit can be linked via anyof its N-terminus, C-terminus, or by an internal amino acid to anothermonomer subunit via any of its N-terminus, C-terminus or an internalamino acid, and linkages may occur via the same or different amino acidresidues on two monomer subunits of a peptide dimer compound. Monomersubunits of peptide dimer compounds can be linked via both theirN-terminus and their C-terminus. The two N-termini of the monomersubunits can be linked; the two C-termini of the monomer subunits can belinked; the N-terminus of the first monomer subunit can be linked to theC-terminus of the second monomer subunit of a peptide dimer compound,and the C-terminus of the first monomer subunit can be linked to theN-terminus of the second monomer subunit of the peptide dimer compound.

A linker can comprise a peptide or a non-peptide. A linker moiety caninclude any suitable structure, length, and/or size. A linker moiety caninclude, for example, DIG, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K,PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Ac, IDA-isovaleric acid, ADAtriazine, triazine-Boc, isophthalic acid, 1,3-phenylenediacetic acid,Glu, Asp, D-Glu, D-Asp, 1,4-phenylenediacetic acid, biphenyl diaceticacid, cyclopropylacetic acid, succinic acid, glutaric acid,dodecanedioic acid, suitable aliphatic diacids, suitable aromaticdiacids, heteroaromatics, and polyethylene glycols having a molecularweight, for example, from 400 Da to 40,000 Da. When a linker is IDA, ADAor any linker with free amine it can be acylated with acylating organiccompound such as 2-me-trifluorobutyl, trifluoropentyl, acetyl, octonyl,butyl, pentyl, hexyl, palmityl, lauryl, oleoyl, lauryl, trifluoromethylbutyric, cyclopentane carboxylic, cyclopropylacetic, 4-fluorobenzoic,4-fluorophenyl acetic, 3-phenylpropionic,tetrahedro-2H-pyran-4-carboxylic, succinic acid, and glutaric acid,straight chain aliphatic acids with 10 to 20 carbon units, cholic acidand other bile acids. A small PEG (PEG4-PEG13), Glu, IsoGlu or Asp canbe used as spacer before acylations.

A linker can connect two monomer subunits by connecting two sulfurcontaining C- or N-terminal amino acids. The two sulfur-containing aminoacids can be connected by a linker comprising a di-halide, an aliphaticchain, or a PEG. A linker can connect two monomeric subunits byconnecting sulfur containing C-terminal amino acids at the C-terminus ofeach monomer subunit. A linker can connect two monomeric subunits byconnecting sulfur containing N-terminal amino acids at the N-terminus ofeach monomer subunit. A linker can connect two monomeric subunits byconnecting a sulfur-containing C-terminal amino acid of one monomersubunit to a sulfur-containing N-terminal amino acid of the othermonomer subunit. The two sulfur-containing amino acids can be connectedby a linker comprising homobifunctional maleimide crosslinkers,di-halide, 1,2-bis(bromomomethyl)benzene,1,2-bis(chloromomethyl)benzene, 1,3-bis(bromomomethyl)benzene,1,3-bis(chloromomethyl)benzene, 1,4-bis(bromomomethyl)benzene,1,4-bis(chloromomethyl)benzene, 3,3′-bis-bromomethyl-biphenyl, or2,2′-bis-bromomethyl-biphenyl. Examples of haloacetyl crosslinkerscontain an iodoacetyl or a bromoacetyl group. These homo bifunctionallinkers may contain spacers comprising PEG or an aliphatic chain. Alinker can be a bifunctional linker (e.g., di-acid, di-amine, dihalide,N-hydroxy succinamine (NHS)-activated diesters, bis-maleimides, whichmay be capable of linking two monomer subunits through amine, ester,thioether, di-thio, or ether bonds.

Examples of suitable linkers include DIG, PEG4, PEG4-biotin, PEG13,PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, ADA, Boc-IDA, glutaricacid, isophthalic acid, 1,3-phenylenediacetic acid,1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, triazine,Boc-triazine, IDA-biotin, PEG4-Biotin, AADA, aliphatics, aromatics,heteroaromatics, and polyethylene glycol-based linkers having amolecular weight from 400 Da to 40,000 Da. Examples of suitablebifunctional linkers include di-acid, di-amine, dihalide, N-hydroxysuccinamine (NHS)-activated diesters, bis-maleimides, which may becapable of linking two monomer subunits through amine, ester, thioether,di-thio, or ether bonds.

Peptide monomers and compounds can form cyclized structures through adisulfide bond, lactam bond, olefin bond, triazole bond, selenoetherbond or a diselenide bond. A cyclized structure of each peptide ligandcan, in some circumstances, increase potency and selectivity of theligands and compounds comprising the ligands.

For example, a heterodimer can comprise an IL-2Rβ ligand provided by thepresent disclosure such as an IL-2Rβ ligand of SEQ ID NOS: 1-193,578-903, 1028-1050, 1052-1064, or 1084, an IL-2Rγc ligand provided bythe present disclosure such as an IL-2Rγc ligand of SEQ ID NOS: 194-267,904-1027, and 1065-1083 and a linker such as a polyethylene glycol-basedlinker having a length from 10 Å to 60 Å.

The individual IL-2Rβ and IL-2Rγc ligands can be linked in various waysto produce heterodimers, that can be evaluated for IL-2R agonistactivity, antagonist activity or other relevant activity. Agonistactivity can depend on heterodimers binding simultaneously to both IL-2Rand IL-2Rγc subunits to induce proximity and orientation compatible withsignaling. Several compound characteristics can influence the activityof heterodimers such as, for example, the linker structure, the linkerlength, the peptide ligand orientation, and the ECD bindingsite-specificity of the monomeric peptides.

Because signaling of the IL-2 receptor may be compatible with a range ofinduced subunit orientations a linker can facilitate binding outside theIL-2R binding site(s). The dimensions of the quaternary complex of IL-2with the IL-2Rα, IL-2R and IL-2Rγc subunits suggest that linkers with alength up to about 50 Å may be useful to connect IL-2Rβ and IL-2Rγcligands to induce productive subunit alignment and agonist activity.

For example, a heterodimer comprising an IL-2Rβ ligand and an IL-2Rγcligand can be attached through a PEG linker. At the terminus of thePEG-linker distal to the peptide, an alkyne functionality can beattached. The other peptide monomer can be functionalized with aterminal azide. The monomers can be coupled utilizing click chemistry,for example, using a 1,3 dipolar Huisgen cycloaddition reaction betweenthe azide and alkyne to form a triazole linkage, under conditionscompatible with maintenance of disulfide bridges that are present incertain peptide ligands. Alkyne and azide groups can be incorporatedinto each monomer using commercially-available amino acid buildingblocks. The spacing between the two peptide ligands can be selectedusing PEG-linkers of various lengths. Using commercially availableFmoc-PEG amino acids, total linker lengths from 10 Å, or less to 50 Å,or more can be synthesized, providing for a wide range heterodimerlinker length diversity.

Induced receptor subunit orientation and the potential for properintra-cellular alignment and signaling can be, in part, a function ofthe orientations in which the peptide ligands link to form theheterodimer. To determine suitable induced subunit orientations, peptideligands can be linked in any of four (4) possible orientations such thatthe C-termini of both subunit binding ligands are coupled through alinker, the N-termini of both subunit binding ligands are coupledthrough a linker, or the N-terminus of one binding subunit can be boundthrough the C-terminus of the other binding subunit (2 scenariospossible) through a suitable linker. Heterodimers can also be linkedthrough amino acid side chains. Heterodimers can also be linked throughamino acid side chains. Heterodimer linkage orientation can beengineered, for example, by synthesizing ligand monomers with the clickfunctionality, i.e., azide or alkyne, and PEG-linker on either the N- oron the C-terminus.

Peptides provided by the present disclosure can include at least oneIL-2Rβ ligand and/or at least one IL-2Rγc ligand. A peptide can include,for example, less than 50 amino acids, which can include the amino acidsconstituting at least one IL-2Rβ ligand and/or at least one IL-2Rγcligand.

A peptide comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand cancomprise, for example, from 5 to 100 amino acids, from 5 to 80 aminoacids, from 5 to 50 amino acids, from 10 to 40 amino acids, from 10 to30 amino acids, or from 15 to 25 amino acids.

In addition to an IL-2Rβ ligand and/or an IL-2Rγc ligand, a peptide caninclude additional amino acids, for example, for establishing theconformation of an IL-2Rβ ligand and/or an IL-2Rγc ligand and/or forcoupling the IL-2Rβ ligand and/or the IL-2Rγc ligand to other compounds.The additional amino acids can be bonded to the N-terminus and/or to theC-terminus of the IL-2Rβ ligand and/or the IL-2Rγc ligand.

Conjugates provided by the present disclosure include at least oneIL-2Rβ ligand and/or at least one IL-2Rγc ligand.

A conjugate can comprise a polypeptide.

A polypeptide can be a single chain peptide having two more IL-2Rβligands and/or two ro more IL-2Rγc ligands. The IL-2Rβ ligands and/orthe IL-2Rγc ligands can be bonded through amino acid linkers.

An amino acid linker can comprise, for example, more than one aminoacid, greater than 5 amino acids, greater than 10 amino acids, greaterthan 50 amino acids, or greater than 100 amino acids. A peptide linkercan comprise, for example, from 1 to 100 amino acids from 3 amino acidsto 75 amino acids, from 5 amino acids to 50 amino acids, or from 10amino acids to 25 amino acids.

For example, in a homodimer, the C-terminus of a first IL-2Rβ ligandand/or IL-2Rγc ligand and the C-terminus of a second IL-2Rβ ligandand/or IL-2Rγc ligand can be attached to the linker; the N-terminus of afirst IL-2Rβ ligand and/or IL-2Rγc ligand and the N-terminus of a secondIL-2Rβ ligand and/or IL-2Rγc ligand can be attached to the linker; orthe C-terminus of a first IL-2Rβ ligand and/or IL-2Rγc ligand and theN-terminus of a second IL-2Rβ ligand and/or IL-2Rγc ligand can beattached to the linker.

A polypeptide comprising an IL-2Rβ ligand and/or IL-2Rγc ligand providedby the present disclosure can comprise, for example, from 5 amino acidsto 4,000 amino acids, from 5 amino acids to 3,000 amino acids, from 5amino acids to 2,500 amino acids, or from 5 amino acids to 2,000 aminoacids.

A polypeptide can be a synthetic peptide or a recombinant polypeptide.

A single chain peptide can be a heteromer having at least one IL-2Rβligand and/or IL-2Rγc ligand in combination with one or more IL-2Rαligands, one or more IL-2Rβ ligands, and/or one or more IL-2Rγc ligands.For example, a single chain peptide can comprise an IL-2Rα ligand, anIL-2Rβ ligand, and/or an IL-2Rγc ligand with amino acid linkers couplingadjacent ligands. A single chain peptide can further include additionalamino acids at the N-terminus and/or C-terminus of the polypeptide.

An IL-2Rα ligand, an IL-2Rβ ligand and/or IL-2Rγc ligand can be arrangedin any order.

Each of the adjacent ligands can independently be coupled through theN-terminus of each ligand, through the C-terminus of each ligand,through the N-terminus and C-terminus of the adjacent ligands, orthrough the side chains of the ligands and/or linkers.

For example, in a heteromer, the C-terminus of an IL-2Rα ligand can beattached to the linker and the N-terminus of an IL-2Rβ ligand or theN-terminus of an IL-2Rγc ligand can be attached to the linker; theC-terminus of an IL-2Rβ ligand or the N-terminus of an IL-2Rγc ligandcan be attached to the linker, or the N-terminus of an IL-2Rα ligand canbe attached to the linker.

The individual IL-2Rβ ligands and/or IL-2Rγc ligands can be linked invarious ways to produce homodimers or homomers, heteromers, that can beevaluated for IL-2R agonist and/or IL-2R antagonist activity. Forexample, homodimers of IL-2Rα ligands or heteromers of an IL-2Rα ligandwith an IL-2Rβ ligands and/or IL-2Rγc can function as an IL-2Rantagonist. Agonist activity can depend on heteromers bindingsimultaneously to both IL-2R and IL-2Rγc subunits to induce proximityand orientation compatible with signaling or inhibition. Severalcompound characteristics can influence the activity of homodimers orheteromers such as, for example, the linker structure, the linkerlength, the peptide ligand orientation, the ECD binding site-specificityof the monomeric peptides, and the affinities of each ligand for therespective receptor subunits. IL-2R agonist and IL-2R antagonistactivity can depend, for example, on increasing the affinity of theIL-2Rα ligand to the IL-2Rα subunit, the IL-2Rβ ligand to the IL-2Rβsubunit, and/or the IL-2Rγc ligand to the IL-2Rγc subunit. Inducedreceptor subunit orientation and the potential for proper intra-cellularalignment and signaling can be, in part, a function of the orientationsin which the peptide ligands link to form the heteromer. To determinesuitable induced subunit orientations, adjacent IL-2R ligands can belinked in any of four (4) possible orientations such that the C-terminiof both subunit binding ligands are coupled through a linker, theN-termini of both subunit binding ligands are coupled through a linker,or the N-terminus of one binding subunit can be bound through theC-terminus of the other binding subunit through a suitable linker.Homomers and heteromers can also be linked through amino acid sidechains. Heteromer linkage orientation can be engineered, for example, bysynthesizing ligand monomers with the click functionality, i.e., azideor alkyne, and PEG-linker on either the N-terminus or on the C-terminus.

A polypeptide can be a synthetically modified polypeptide comprising oneor more IL-2Rβ ligands and/or one or more IL-2Rγc ligands. Themodifications can influence, for example, the activity of thepolypeptide or the pharmacokinetics of the polypeptide. Examples includepolypeptides incorporating polyethylene glycol moieties or albuminbinding moieties.

Compounds comprising an IL-2Rβ ligand, an IL-2Rγc ligand, or both anIL-2Rβ ligand and an IL-2Rγc ligand include fusion proteins.

An IL-2Rβ ligand and/or an IL-2Rγc ligand can be fused to anotherprotein that imparts a desired functionality to the construct. Forexample, the protein can impart a desired pharmacokinetic profile or canbe designed to target specific antigens.

Examples of suitable fusion partners include Fc fusion proteins, IgGfusion proteins, human serum albumin (HSA) fusion proteins, other humanproteins and mutants and/or variants thereof; and hydrophilic,biodegradable protein polymers. A fusion protein partner can be anaturally occurring protein, a modified-naturally occurring protein, ora synthetic protein.

For example, an IL-2Rβ ligand and/or an IL-2Rγc ligand provided by thepresent disclosure can be fused to a protein that increases thecirculating half-life of the compound. Fusion of therapeutic proteinswith the IgG or IgG Fc domain accomplishes this by increasing thehydrodynamic radius of the protein, thus reducing renal clearance, andthrough Neonatal Fc Receptor (FcRn)-mediated recycling of the fusionprotein, thus prolonging the circulating half-life. Other fusionproteins can be designed to modify properties such as thepharmacokinetics, biodistribution, pharmacodynamics, pharmacology,cytotoxicity, and/or targeting.

A fusion protein provided by the present disclosure can comprise apeptide, or multiple tandem peptides provided by the present disclosurelinked to one or more fusion protein partners. A fusion protein partnercan be linked to the N-terminus and/or the C-terminus of tandempeptides. One or more fusion protein partners can be linked to theN-terminus and/or the C-terminus of tandem peptides. An IL-2Rβ ligandand/or an IL-2Rγc ligand can be linked to one or more fusion proteinpartners, where each of the fusion protein partners can be the same orsome of the fusion protein partners can be different than other of thefusion protein partners linked to a peptide.

The amino acid sequence at the junction between an IL-2Rβ ligand and/orIL-2Rγc ligand and a fusion partner protein can be either a directfusion of the two protein sequences or a fusion with an interveninglinker peptide. Linker peptides can be included as spacers between thetwo protein moieties. Linker peptides can promote proper protein foldingand stability of the component protein moieties, improve proteinexpression, and enhance bioactivity of the component protein moieties.Peptide linkers used in fusion proteins can be designed to beunstructured flexible peptides. Peptide linkers can be, for example,rich in glycine and serine, such as repeats of a sequence such as, forexample, GS, GGS, GGGS (SEQ ID NO: 1085), GGGGS (SEQ ID NO: 1086),(GGGGs)3 (SEQ ID NO: 1087), (Gly)8 (SEQ ID NO: 1088), (Gly)6 (SEQ ID NO:1089), (EAAAK)1-3 (SEQ ID NO: 1090), A(EAAAK)4ALEA(EAAAK)4A (SEQ ID NO:1091), PAPAP (SEQ ID NO: 1092), AEAAAKEAAAKA (SEQ ID NO: 1093),(Ala-Pro)a (10-34 aa) (SEQ ID NO: 1094), disulfide, VSQTSKLTR AETVFPDV(SEQ ID NO: 1095), PLG LWA (SEQ ID NO: 1096), and GFLG (SEQ ID NO:1097), RVQDVIERFWDFIDQLSGSGSGK (SEQ ID NO: 1098), andVDADGPLARLKKAIFSPGSGSGK (SEQ ID NO: 1099), (PA)n where n is an integer 1to 20 (SEQ ID NO: 1100) such as (PA)10 (SEQ ID NO: 1101), and (GS)nwhere n is an integer from 1 to 20 (SEQ ID NO: 1102) such as (GS)10 (SEQID NO: 1103). A flexible linker peptide with a fully extended β-strandconformation can have an end-to-end length of approximately 3.5 Å perresidue. Thus, a linker peptide of 5, 10, 15, or 10 residues will have amaximum fully extended length of 17.5 Å, 35A, 52.5 Å, 70A, 140 Å, ormore than 140 Å, respectively.

A linker peptide can facilitate obtaining an appropriate conformationand orientation of individual fusion protein moieties to facilitate theengagement of the IL-2Rβ ligand and/or IL-2Rγc ligand with the IL-2Rβsubunit and/or IL-2Rγc subunit, facilitate binding of the IL-2Rβ ligandand/or IL-2Rγc ligand to the IL-2 receptor, enable fusion proteinrecycling, and prolong the circulating half-life of the active moiety.Because the factors influencing these interactions are difficult topredict, the requirement for and the proper length of a linker peptidemust be empirically tested and determined.

There are multiple options for the design and construction of a fusionprotein comprising an IL-2R and/or an IL-2Rγc ligand and which can beselected to obtain a molecule having the desired biological activity andpharmaceutical characteristics. Design options include, for example, thenature of the IL-2 selective agonist, the choice of the partner proteinmoiety, the configuration of fusion partners in the fusion protein, andthe amino acid sequence at the junction between the IL-2R ligand and thefusion partner protein.

In general, preparation of the fusion proteins provided by the presentdisclosure can be accomplished by recognized recombinant DNA techniquesinvolving, for example, polymerase chain amplification reactions (PCR),preparation of plasmid DNA, cleavage of DNA with restriction enzymes,preparation of oligonucleotides, ligation of DNA, isolation of mRNA,introduction of the DNA into a suitable cell, transformation ortransfection of a host, and culturing of the host. Additionally, fusionproteins can be isolated and purified using chaotropic agents and wellknown electrophoretic, centrifugation, and chromatographic methods.

Genes encoding fusion proteins provided by the present disclosure caninvolve restriction enzyme digestion and ligation as the basic stepsemployed to yield DNA encoding the desired fusions. The ends of the DNAfragment may require modification prior to ligation, and this may beaccomplished by filling in overhangs, deleting terminal portions of thefragment(s) with nucleases (e.g., ExoIII), site directed mutagenesis, orby adding new base pairs by PCR. Polylinkers and adaptors may beemployed to facilitate joining of selected fragments. The expressionconstruct can be assembled in stages employing rounds of restriction,ligation, and transformation of E. coli. Numerous cloning vectorssuitable for construction of the expression construct are known in theart. The selection of a cloning vector can be influenced by the genetransfer system selected for introduction of the expression constructinto the host cell. At the end of each stage, the resulting constructmay be analyzed by restriction, DNA sequence, hybridization and PCRanalyses.

Site-directed mutagenesis can be used to introduce specific mutationsinto the genes encoding the fusion proteins provided by the presentdisclosure by methods known in the art. Any suitable site-directedmutagenesis procedure can be used in the present invention. There aremany commercial kits available that can be used to prepare the variantsof this invention.

Various promoters (transcriptional initiation regulatory region) may beused according to the invention. The selection of the appropriatepromoter can depend on the proposed expression host. Promoters fromheterologous sources may be used as long as they are functional in thechosen host.

Various signal sequences may be used to facilitate expression of theproteins described herein. Signal sequence are selected or designed forefficient secretion and processing in the expression host may also beused. A signal sequence which is homologous to the human IL-2 codingsequence may be used for mammalian cells. Other suitable signalsequence/host cell pairs include the B. subtilis sacB signal sequencefor secretion in B. subtilis, and the Saccharontyces cerevisiae α-matingfactor or P. pastoris acid phosphatase phoI signal sequences for P.pastoris secretion. The signal sequence may be joined directly throughthe sequence encoding the signal peptidase cleavage site to the proteincoding sequence, or through a short nucleotide bridge.

Elements for enhancing transcription and translation have beenidentified for eukaryotic protein expression systems. For example,positioning the cauliflower mosaic virus (CaMV) promoter 1000 bp oneither side of a heterologous promoter may elevate transcriptionallevels by 10- to 400-fold in plant cells. The expression constructshould also include the appropriate translational initiation sequences.Modification of the expression construct to include a Kozak consensussequence for proper translational initiation may increase the level oftranslation by 10-fold.

The expression cassettes are joined to appropriate vectors compatiblewith the host that is being employed. The vector must be able toaccommodate the DNA sequence coding for the fusion proteins to beexpressed. Suitable host cells include eukaryotic and prokaryotic cells,such as those cells that can be easily transformed and exhibit rapidgrowth in culture medium. Examples of suitable host cells includeprokaryotes such as E. coli, Bacillus subtillus, etc. and eukaryotessuch as animal cells and yeast strains, e.g., S. cerevisiae. Suitablemammalian cells include HEK, J558, NSO, SP2-O or CHO. Other suitablehosts include, e.g., insect cells such as Sf9. Conventional culturingconditions can be employed. Stable transformed or transfected cell linescan then be selected. In vitro transcription-translation systems canalso be employed as an expression system.

Nucleic acids encoding a desired fusion protein can be introduced into ahost cell by standard techniques for transfecting cells. The term“transfecting” or “transfection” is intended to encompass allconventional techniques for introducing nucleic acid into host cells,including calcium phosphate co-precipitation, DEAE-dextran-mediatedtransfection, lipofection, electroporation, microinjection, viraltransduction and/or integration.

Alternatively, one can use synthetic gene construction for all or partof the construction of the fusion proteins described herein. This canentail in vitro synthesis of a designed polynucleotide molecule toencode a polypeptide molecule of interest. Gene synthesis can beperformed utilizing a number of techniques, such as the multiplexmicrochip-based technology and similar technologies whereinoligonucleotides are synthesized and assembled upon photo-programmablemicrofluidic chips.

Fusion proteins provided by the present disclosure can be isolated fromharvested host cells or from the culture medium. Standard proteinpurification techniques are used to isolate the proteins of interestfrom the medium or from the harvested cells. For example, thepurification techniques can be used to express and purify a desiredfusion protein on a large-scale (i.e., in at least milligram quantities)from a variety of approaches including roller bottles, spinner flasks,tissue culture plates, bioreactor, or a fermenter.

Compounds provided by the present disclosure comprise at least oneIL-2Rβ ligand and/or at least one IL-2Rγc ligand. Compounds cancomprise, for example, from 1 to 10 IL-2Rβ ligands and/or IL-2Rγcligands, from 1 to 6 IL-2Rβ ligands and/or IL-2Rγc ligands, or from 1 to3 IL-2Rβ ligands and/or IL-2Rγc ligands. Examples of compoundscomprising an IL-2Rβ ligand and/or IL-2Rγc ligand include peptides andconjugates. Examples of conjugates include one or more IL-2Rβ ligands,and/or one or more IL-2Rγc ligands bound to a polypeptide, amacromolecule such as a polyethylene glycol, a fusion protein, or abiological molecule such as an antibody.

Functionally, compounds comprising at least one IL-2Rβ ligand and/or atleast one IL-2Rγc ligand can be IL-2Rβγc agonists, IL-2Rαβγc agonists,IL-2Rβγc antagonists, IL-2Rαβγc antagonists, diagnostic reagents,imaging reagents, targeting compounds, cytotoxic compounds, andcompounds exhibiting dual pharmacology.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand providedby the present disclosure can have a molecular weight, for example, from1,000 to 400,000 Da, from 1,000 to 200,000 Da, from 1,000 to 100,000 Da,from 1,000 Da to 20,000 Da, from 1,500 Da to 15,000 Da, from 2,000 Da to10,000 Da, or from 5,000 Da to 10,000 Da.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand providedby the present disclosure can be attached to one or more moieties thatimpart a property to the compound that enhances therapeutic efficacy.Examples of properties include potency, aqueous solubility, polarity,lipophilicity, pharmacokinetics, targeting, bioavailability,pH-dependent binding, bioactivity, pharmacodynamics, cellular activity,metabolism, efficacy, reversible incapacitation (caging), selectivity,or a combination of any of the foregoing.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand cancomprise one or more moieties that are cleavable in vivo. The moiety canbe cleavable in a target specific environment such as, for example, by atarget specific or target enriched enzyme, or pH. The moiety can becleavable upon exposure to electromagnetic energy such as visible lightor infrared radiation and/or by exposure to thermal energy.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand caninclude a polymer, a peptide, or an antibody.

Compounds comprising an IL-2Rβ ligand and/or IL-2Rγc an ligand caninclude a tumor-targeting moiety such as, for example, a tumor-specificantibody, a tumor-specific antibody fragment, a tumor-specific protein,a tumor-specific peptide, a non-peptidyl tumor cell ligand, or acombination of any of the foregoing.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand caninclude an immune cell-targeting moiety such as, for example, an immunecell-specific antibody, an immune cell-specific antibody fragment, animmune cell-specific protein, an immune cell-specific peptide, anon-peptidyl immune cell-ligand, or a combination of any of theforegoing.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand cancomprise a caged molecule or molecules. A caged molecule can in effectencapsulate the compound and can serve to prevent bioactivity in certaintissues, for example, to protect peripheral tissues from the toxicity ofIL-2Rαβγc activation.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand cancomprise a moiety, wherein the moiety comprises a small molecule, apeptide, a polymer, or an antibody. The small molecule can be anon-peptidyl molecule. The moiety can exhibit a pharmacological effect.The pharmacological effect can manifest when the moiety is bound to theIL-2Rβ ligand and/or the IL-2Rγc ligand and/or after the moiety iscleaved from the compound comprising an IL-2Rβ ligand and/or the IL-2Rγcligand.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand cancomprise a moiety configured to sustain a circulating reservoir of thecompound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand cancomprise a moiety configured to target the IL-2R-directedimmuno-stimulation of the effector immune cells in a tumor.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand cancomprise a moiety configured to target specific immune cells such asTreg cells.

The moiety can comprise a compound that is toxic to a cell targeted bythe compound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand. Thetoxic moiety can be cleavable or otherwise activated such as by exposureto electromagnetic radiation. The toxic moiety can be activated, forexample, by exposure to electromagnetic radiation such as visibleradiation or ultraviolet radiation. Compounds comprising an IL-2Rβligand and/or an IL-2Rγc ligand provided by the present disclosure canactivate the IL-2 receptor. Compounds comprising an IL-2Rβ ligand and/orIL-2Rγc ligand provided by the present disclosure can inhibit the IL-2receptor. Certain compounds comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand provided by the present disclosure can bind to the IL-2Rβsubunit and/or to the IL-2Rγc subunit and prevent other compounds frombinding to the IL-2Rβ subunit and/or the IL-2Rγc subunit. Compoundscomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand can reduce thepotency of or interfere with the binding of IL-2R agonists to cells thathighly express the IL-2Rβ subunit and/or the IL-2Rγc subunit. Compoundscomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand can reduce thesensitivity of cells to IL-2.

Compounds comprising an IL-2Rβ ligand and/or IL-2Rγc ligand provided bythe present disclosure can include compounds that act as IL-2Rβγcagonists or IL-2Rαβγc agonists.

An IL-2Rβγc agonist or an IL-2Rαβγc agonist provided by the presentdisclosure can comprise synthetic peptides or recombinant peptideslinked in tandem to create a single chain peptide comprising an IL-2Rβligand, an IL-2Rγc ligand and, in the case of an IL-2Rαβγc agonist, anIL-2Rα ligand. The ligands can be in any order and can be separated byamino acid linkers. The synthetic peptides can comprise natural aminoacids or peptides with natural amino acids and suitable substitutionswith unnatural amino acids. IL-2Rβγc agonists and IL-2Rαβγc agonistsprovided by the present disclosure can be a recombinant fusion proteincomprising an IL-2Rγc ligand and an IL-2Rβ ligand, and in the case of anIL-2Rαβγc agonist, an IL-2Rα ligand, and a fusion partner such as an Fcprotein, an IgG protein, human serum albumin or other natural ordesigned protein, or a hydrophilic, biodegradable protein polymer. AnIL-2Rβγc agonist or an IL-2Rαβγc agonist can comprise one or more IL-2Rβligands and/or one or more IL-2Rγc ligands and, in the case of anIL-2Rαβγc agonist, one or more IL-2Rα ligands. An IL-2Rβγc agonist or anIL-2Rαβγc agonist can comprise an IL-2Rβ ligand and an IL-2Rγc ligandand, in the case of an IL-2Rαβγc agonist, an IL-2Rα ligand, and canfurther include one or more moieties selected to modify thepharmacokinetics of the IL-2R agonist such as PEG or an albumin bindingmoiety.

An IL-2Rβγc agonist can bind to IL-2Rβ subunit and IL-2Rγc subunit andcan activate the IL-2 receptor. The binding affinity (IC₅₀) of theIL-2Rβγc agonist to the IL-2Rβ subunit and IL-2Rγc subunit canindependently be, for example, less than 100 μM, less than 10 μM, lessthan 1 μM, less than 100 nM, less than 10 nM, or less than 1 nM. AnIL-2Rβγc agonist can bind to IL-2Rβ and IL-2Rγc either competitively ornon-competitively with IL-2.

An IL-2Rαβγc agonist can bind to IL-2Rα, IL-2Rβ, and IL-2Rγc andactivate the IL-2 receptor. The binding affinity (IC₅₀) of the IL-2Rαβγcagonist to IL-2Rα, IL-2Rβ, and IL-2Rγc can be, for example, less than100 μM, less than 10 μM, less than 1 μM, less than 100 nM, less than 10nM, or less than 1 nM. An IL-2Rαβγc agonist can bind to IL-2Rα, IL-2Rβ,and IL-2Rγc either competitively or non-competitively with IL-2.

An IL-2Rβγc agonist or an IL-2Rαβγc agonist comprising an IL-2Rβ ligandand an IL-2Rγc ligand and, in the case of an IL-2Rαβγc agonist, anIL-2Rα ligand, can be configured to more potently activate cellsexpressing the IL-2Rβ subunit and the IL-2Rγc subunit, therebyfacilitating the ability to differentially activate IL-2R expressed onthe surface of different cell types by controlling dose of the agonist.For example, when incubated with a heteromeric compound comprising anIL-2Rβ ligand and IL-2Rγc ligand, primary human peripheral bloodmononuclear cells (PBMC) expressing the IL-2Rαβγc subunit phosphorylatetranscription 5 (STAT5). A heteromer can comprise an IL-2Rβ ligand, anIL-2Rγc ligand, and a linker, where the linker is configured such thatthe heteromer is an agonist for the IL-2 receptor. A linker can comprisea length that facilitates binding of an IL-2Rβ ligand and an IL-2Rγcligand to the IL-2 receptor. For example, a linker can have a lengthfrom 10 Å to 400 Å, from 10 Å to 300 Å, from 10 Å to 200 Å, 20 Å to 100Å, from 30 Å to 80 Å, or from 40 Å to 60 Å. A linker can comprise achemical structure that facilitates simultaneous binding of an IL-2Rβligand and an IL-2Rγc ligand to the respective IL-2 receptor subunits.For example, a linker can comprise a peptide or a hydrocarbon.

An IL-2Rβγc agonist or an IL-2Rαβγc agonist can partially activate theIL-2 receptor. Partial activation refers to a level of activation, thatis, for example, less than 75% of maximum activation, less than 50%,less than 25%, less than 10%, or less than 1% of the maximum activation.Maximum activation (E_(max)) is the amplitude of cellular signal(activation) achievable at high agonist concentration such as a highconcentration of IL-2. Partial IL-2R agonists can be effective inmodulating the levels of response of IL-2R to activation of the IL-2Rβand IL-2Rγc subunits among different cell types expressing IL-2R. Forexample, different cell types are known to vary in expression levels ofeach of the IL-2R subunits, IL-2Rα, IL-2Rβ, and IL-2Rγc, and to exhibitdifferent sensitivities to IL-2R agonists.

An IL-2R agonist comprising one or more IL-2Rα ligands, one or moreIL-2Rβ ligands, and one or more IL-2Rγc ligands can exhibit increasedbinding and potency on cells expressing the IL-2Rα subunit (such asTregs).

An IL-2Rαβγc agonist can comprise an IL-2Rα ligand and modified IL-2Rβligands and/or IL-2Rγc ligands. Modified IL-2Rβ and IL-2Rγc ligands canbe selected or designed to bind and activate IL-2R, but with low ormodest affinity and potency to IL-2R. Such IL-2Rαβγc agonists can havegreater differential sensitivity for IL-2R activation between cells thathighly express IL-2Rα and cells having a low level of IL-2Rα expression;for example, between Tregs that have a high expression of IL-2Rα andTeff cells that have a low expression level of IL-2Rα.

An IL-2Rβγc agonist or an IL-2Rαβγc agonist can comprise one or moreIL-2Rβ ligands and/or one or more IL-2Rγc ligands and in the case of anIL-2Rαβγc agonist, one or more IL-2Rα ligands. The presence of multipleIL-2Rα ligands, IL-2Rβ ligands and/or IL-2Rγc ligands can preferentiallyincrease the potency of the IL-2R agonists on cells that highly expressIL-2Rα, IL-2Rβ and/or IL-2Rγc compared to cells having low expressionlevels of IL-2Rα, IL-2Rβ, and/or IL-2Rγc.

An IL-2R agonist can comprise a moiety having an additionalpharmacological activity other than that mediated by activation of theIL-2 receptor. The pharmacological activity can be an activity that hasa therapeutic efficacy that is synergistic with that of the IL-2Ragonist or the pharmacological activity can be an activity that has atherapeutic efficacy that is not synergistic with that of the IL-2Ragonist. For example, a moiety or molecule having a usefulpharmacological activity can comprise a checkpoint inhibitor.

Compounds provided by the present disclosure include IL-2Rβ antagonistsand IL-2Rγc antagonists. An IL-2R antagonist is a compound comprising anIL-2Rβ ligand or an IL-2Rγc ligand that inhibits binding of IL-2 andmutants and modified forms thereof, to the IL-2Rβ subunit or to theIL-2Rγc subunit and/or diminishes IL-2 activation of the IL-2 receptor.

IL-2Rβ antagonists and IL-2Rγc antagonists can attenuate the sensitivityof cells expressing the IL-2Rβ subunit and/or the IL-2Rγc subunit toactivation by IL-2 or mutants and modified forms thereof.

IL-2Rβ antagonists and IL-2Rγc antagonists can include compounds havingmore than one IL-2Rβ ligand or more than one IL-2Rγc ligand and can bindcompetitively or non-competitively with IL-2 to the IL-2 receptor.

IL-2Rβ antagonists and IL-2Rγc antagonists can comprise one or moreIL-2Rβ ligands or one or more IL-2Rγc ligands and a moiety having auseful pharmacological activity. The moiety can exhibit apharmacological activity that is synergistic with IL-2R inhibition or isnot synergistic with inhibition of IL-2R.

IL-2Rβ antagonists and IL-2Rγc antagonists can further includerecombinant fusion proteins.

Compounds provided by the present disclosure include IL-2R antagonists.

An IL-2R antagonist can comprise an IL-2Rα ligand and an IL-2Rβ ligand;an IL-2Rα ligand and an IL-2Rγc ligand; or an IL-2Rβ ligand and anIL-2Rγc ligand.

IL-2R antagonists include compounds that bind to either the IL-2Rβ orIL-2Rγc subunit and inhibit activation of the IL-2 receptor.

IL-2R antagonists include compounds that bind to the IL-2Rβ and theIL-2Rγc subunits and inhibit activation of the IL-2 receptor, where theIL-2Rβ and IL-2Rγc ligands are configured to not activate the IL-2receptor. Such compounds are high affinity antagonists for IL-2Ractivation and the presence of both IL-2R and IL-2Rγc ligands enhancesthe potency of the IL-2R antagonists.

IL-2R antagonists include compounds comprising an IL-2Rβ ligand, and anIL-2Rγc ligand, which are configured to exhibit partial activation ofthe IL-2 receptor. These compounds are examples of partial IL-2Rantagonists. Such compounds are useful for modulating the level ofresponse of cells to IL-2R agonists among cells having differentexpression levels of IL-2R subunits. Use of the partial IL-2Ragonists/antagonists can modulate the response of cells to IL-2Ragonists among cells having different expression levels of the IL-2Rβ,and/or IL-2Rγc subunits.

An IL-2R antagonist can comprise one or more IL-2Rβ and/or IL-2Rγcligands. An IL-2R antagonist can be a peptide or a polypeptide, whichcan be synthetic or recombinant. The IL-2R ligands can be coupled in anyorder, in any orientation, and can be coupled with linkers. The linkerscan comprise natural and/or unnatural amino acids and/or non-peptidylstructures.

An IL-2R antagonist can be chemically modified to include, for example,moieties that affect the pharmacokinetics of the IL-2R antagonist suchas PEG and albumin-binding moieties.

IL-2R antagonists can further include recombinant fusion proteins.

Compounds comprising an IL-2Rβ ligand and/or IL-2Rγc ligand includediagnostic reagents. As a diagnostic agent, a compound comprising anIL-2Rβ ligand and/or IL-2Rγc ligand can be used to detect and/or tomeasure cells expressing the IL-2Rβ subunit and/or IL-2Rγc subunit. Thecompounds can be used to determine the level of IL-2Rβ and/or IL-2Rγcexpression of a cell, or population of cells, or of a tissue. Thecompounds can be used to assess the binding affinity of the IL-2Rβsubunit and/or IL-2Rγc subunit to a cell or population of cells. Thecompounds may be used to determine the particular type of cell, forexample, based on IL-2Rβ and/or IL-2Rγc expression levels.

The compounds can be useful for in vitro and in vivo diagnostics.

A diagnostic compound comprising an IL-2Rβ ligand and/or IL-2Rγc ligandcan comprise a detectable marker. The detectable marker can be cleavableor non-cleavable.

A detectable marker can comprise, for example, a radiolabel, afluorescent label, an enzymatic label.

A diagnostic compound comprising an IL-2Rβ ligand and/or IL-2Rγc ligandcan be used to measure cells expressing the IL-2Rβ subunit and/orIL-2Rγc subunit and/or the level of expression of cells expressing theIL-2Rβ subunit and/or IL-2Rγc subunit in a biological sample such as asample of blood of a patient. Measurements can be made, for example,using flow cytometry. The number of cells expressing the IL-2Rβ subunitand/or IL-2Rγc subunit and/or the expression level of the IL-2Rβ subunitand/or IL-2Rγc subunit, when correlated with a disease in a patient or apharmacologically significant parameter of the disease in a patient canbe used to inform treatment of the disease. For example, if a level ofexpression of the IL-2Rβ subunit and/or IL-2Rγc subunit is above orbelow a therapeutically meaningful threshold for a particular disease, acompound comprising an IL-2Rβ ligand and/or IL-2Rγc ligand provided bythe present disclosure can be administered to the patient to treat thedisease.

Compounds comprising an IL-2Rβ ligand and/or IL-2Rγc ligand can beattached to a solid support. Based on the ability of the compounds tobind to the IL-2Rβ subunit and/or IL-2Rγc subunit, the compounds can beused as reagents for detecting IL-2Rβ subunits and/or IL-2Rγc subunits,for example, on living cells, fixed cells, in biological fluids, intissue homogenates, in purified, and natural in biological materials. Inaddition, based on their ability to bind the IL-2Rβ subunit and/orIL-2Rγc subunit, the peptides of the present invention can be used, forexample, in in situ staining, FACS (fluorescence-activated cellsorting), Western Blotting, and ELISA. In addition, compounds providedby the present disclosure can be used in receptor purification, or topurify cells expressing the IL-2Rβ subunit and/or IL-2Rγc subunit on thecell surface.

Compounds comprising an IL-2Rβ ligand and/or IL-2Rγc ligand provided bythe present disclosure can also be used as reagents for various medicalresearch and diagnostic uses. Such uses include, for example, use as acalibration standard for quantitating the activities of candidate IL-2Ragonists or IL-2R antagonists in functional assays; use to maintain theproliferation and growth of IL-2-dependent cell lines; (3) use instructural analysis of the IL-2 receptor through co-crystallization; useto investigate the mechanism of IL-2 signal transduction/receptoractivation; and other research and diagnostic applications wherein theIL-2 receptor is implicated.

Assessing single patient response to therapy and qualifying a patientfor optimal therapy are among the greatest challenges of modernhealthcare and relate to trends in personalized medicine. A compoundcomprising an IL-2Rβ ligand and/or IL-2Rγc ligand can have targetselectivity for diseases in which cells associated with the etiology ofthe disease express the IL-2Rβ subunit and/or IL-2Rγc subunit. Forexample, a compound comprising an IL-2Rβ ligand and/or IL-2Rγc ligandradiolabeled for positron emission tomography (PET) or single photonemission computed tomography (SPECT) can be used to predict thetargeting of the treatment based on a single-study, case-by-case patientanalysis thus excluding subjects that are expected not to benefit fromtreatment with a therapeutic compound affecting the activity of theIL-2Rβ subunit and/or IL-2Rγc subunit. PET/SPECT scans usingradiolabeled a compound comprising an IL-2Rβ ligand and/or IL-2Rγcligand, once correlated to the concentration of a compound comprising anIL-2Rβ ligand and/or IL-2Rγc ligand can provide a three-dimensionaldistribution map, which can then be used for macroscopic dosecalculations.

Compounds comprising an IL-2Rβ ligand and/or IL-2Rγc ligand can compriseone or more imaging agents. The IL-2Rβ ligand and/or IL-2Rγc ligand candirect and localize the compound to cells, populations of cells, andtissue expressing the IL-2Rβ subunit and/or IL-2Rγc subunit. The imagingcompounds can comprise one or more imaging agents such as radiolabels,fluorescent labels, enzymatic labels, or PET imaging agents.

The imaging agents can be used to determine the number of cellsexpressing the IL-2Rβ subunit and/or IL-2Rγc subunit, the expressionlevel of cells expressing the IL-2Rβ subunit and/or IL-2Rγc subunit, orproperties of the IL-2Rβ subunit and/or IL-2Rγc subunit such as theaffinity of the IL-2Rβ subunit and/or IL-2Rγc subunit to a particularIL-2Rβ ligand and/or IL-2Rγc ligand and/or compound comprising an IL-2Rβligand and/or an IL-2Rγc ligand. The imaging agents can be used, forexample, to evaluate cancer cells expressing the IL-2Rβ subunit and/orthe IL-2Rγc subunit, or to evaluate Treg and/or Teff cells.

The label can be detected to determine a biodistribution of the compoundin a patient or to assess the potential for therapeutic efficacy. Forexample, tumors expressing high levels of the IL-2R receptor and/or theIL-2Rβ subunit and/or IL-2Rγc subunit may be attractive targets fortherapeutic compounds comprising an IL-2Rβ ligand and/or IL-2Rγc ligandprovided by the present disclosure.

The imaging agents can be used to evaluate cells expressing the IL-2Rβsubunit and/or the IL-2Rγc subunit before therapy, during therapy,and/or following therapy.

Imaging agents comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand canfurther comprise a moiety capable of binding to a cell surface and inparticular to a protein expressed on the cell surface. The protein canbe indicative of a certain cell type and is referred to as a cellsurface marker. Imaging agents comprising both an IL-2Rβ ligand and/oran IL-2Rγc ligand and a cell surface marker can be used to assess cells,a population of cells, and/or a tissue expressing both the IL-2Rβsubunit and/or IL-2Rγc subunit and the cell surface marker. Assessmentcan include determining the number of cells expressing both the IL-2Rβsubunit and/or the IL-2Rγc subunit and the cell surface marker, theexpression levels of the IL-2Rβ subunit and/or the IL-2Rγc subunit andthe cell surface marker, and/or the affinity of the imaging agent to theIL-2Rβ subunit and/or the IL-2Rγc subunit and/or the cell surfacemarker.

The imaging agents can be used to evaluate cells expressing the IL-2Rβsubunit and/or the IL-2Rγc subunit and the cell surface marker beforetherapy, during therapy, and/or following therapy.

As a practical example, T-cell infiltration of tumor lesions is a knownprognostic factor in several tumor types and is used as a treatmentmechanism in some of these tumor types. For example, in metastaticmelanoma, treatment with immune checkpoint inhibitors induces clinicalbenefit in about 30-50% of the patients. Tumor-infiltrating T-cellsexpress the IL-2 receptor on their surface. Therefore, these T-cells canbe visualized by molecular imaging with a compound comprising an IL-2Rβligand and/or an IL-2Rγc ligand and a radiolabel such as a PET tracer.

As another example, IL-2 is synthesized and secreted by activated Tlymphocytes, especially CD8+ CTL and CD4+ Thl lymphocytes. T lymphocyteactivation is observed in many types of inflammatory diseases, such asinflammatory degenerative diseases, graft rejection, tumor inflammation,organ-specific autoimmune diseases, and adipose inflammatory insulinresistance. IL-2 binds with high affinity to the cell membrane IL-2receptor, which is mainly expressed on the cell surface of activated Tlymphocytes. PET imaging of activated T lymphocytes by radiolabeledIL-2Rβ ligand and/or IL-2Rγc ligand therefore provides an in vivo,dynamic approach in studying the immune-cell infiltration in theseinflammatory diseases.

Compounds provided by the present disclosure can be labeled. Labeledcompounds can be useful in diagnostics.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand andselective IL-2Rβγc agonists provided by the present disclosure can belabeled with a detectable marker. The label can be used to determine abiodistribution of the compound in a patient or to assess the potentialfor therapeutic efficacy. For example, tumors expressing high levels ofthe IL-2R receptor may be attractive targets for selective IL-2Rβγcagonists and compounds comprising an IL-2Rβ ligand and/or an IL-2Rγcligand provided by the present disclosure.

Thus, compounds provided by the present disclosure include labeledcompounds. A labeled compound can be a detectable marker, for example, aradiolabeled amino acid or an attachment of biotinyl moieties to apolypeptide, wherein said attached biotinyl moieties can be detected bymarked avidin (e.g., streptavidin containing a fluorescent marker orenzymatic activity that can be detected by optical or colorimetricmethods). Various methods of labeling polypeptides and glycoproteins areknown in the art and may be used. Examples of labels for polypeptidesinclude, for example, a radioisotope such as, ³H, ¹⁴C, ³⁵S, ¹²⁵I, and¹³¹I, a fluorescent labels such as FITC, rhodamine, and lanthanidephosphors, an enzymatic label such as horseradish peroxidase,β-galactosidase, luciferase, and alkaline phosphatase, biotinyl groups,predetermined polypeptide epitopes recognized by a secondary reportersuch as leucine zipper pair sequences, binding sites for secondaryantibodies, metal ligands, and epitope tags. A label can be attached byspacer arms of various lengths to reduce potential steric hindrance.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand cancomprise a cell-specific targeting moiety or molecule.

A cell-specific targeting moiety can comprise a moiety that has anaffinity for a component on the surface of a cell such as a receptor, aprotein, or an epitope. A moiety can comprise, for example, a ligand oran antibody having an affinity to a cell surface component.

The targeting moiety can direct and concentrate compounds comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand at the cells, population ofcells, or tissue targeted by the targeting moiety.

The targeting moiety can enhance the potency of IL-2R agonism or IL-2Rantagonism for the cells or population of cells being targeted.

The targeting moiety can provide a differential response to IL-2Ragonism or to IL-2R antagonism between the cells being targeted and thecells not being targeted by the targeting moiety.

The targeting moiety can provide a differential response to IL-2Ragonism or IL-2R antagonism between cells having a high expression levelof the targeted component and cells having a lower expression level ofthe targeted component.

Compounds comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand canfurther comprise a bioactive moiety or a bioactive molecule. A compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand can be used todeliver the bioactive moiety or bioactive molecule to cells, to apopulation of cells, or to a tissue expressing the IL-2Rβ subunit and/orthe IL-2Rγc subunit.

The bioactive moiety or molecule can be non-cleavable and capable ofexerting a biological activity when bound to the compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand.

The bioactive moiety or molecule can be cleavable. The moiety can becleavable by any suitable mechanism such as by pH, enzymatic, thermal,and/or electromagnetic mechanisms. Electromagnetic mechanisms include,for example, exposing the compounds to infrared, visible, or ultravioletradiation, where the bioactive moiety is attached to the compoundscomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand through aphotolabile moiety capable of being cleaved by the radiation.

The bioactive molecule can be non-cleavable but otherwise activatable,such as for example, activatable by exposure to electromagneticradiation.

IL-2Rβ ligands and/or IL-2Rγc ligands can be selected to have enhancedbinding to the IL-2Rβ subunit and/or to the IL-2Rγc subunit at a certainpH. For example, a pH-selective IL-2Rβ ligand and/or IL-2Rγc ligand canhave a greater affinity to the IL-2Rβ subunit and/or IL-2Rγc subunit,respectively, at low pH commensurate with that of a solid tumormicroenvironment. Compounds comprising low-pH selective IL-2Rβ ligandsand/or IL-2Rγc ligands can be used to preferentially activate cells inlow pH environments expressing the IL-2Rβ subunit and/or the IL-2Rγcsubunit compared to cells in normal pH environments associated withhealthy tissue.

Thus, compounds comprising selective IL-2Rβ ligands and/or IL-2Rγcligands such as pH-selective IL-2Rβ ligands and/or pH-selective IL-2Rγcligands can be used with other pH-selective bioactive moieties andmolecules.

A bioactive moiety or bioactive molecule can itself be selective for aparticular cell population. For example, a bioactive moiety or bioactivemolecule can exhibit a greater or lesser affinity, potency, and/oractivity at the cell being targeted by a selective IL-2Rβ ligand and/orIL-2Rγc ligand. For example, the bioactive moiety or molecule canexhibit greater bioactivity in a low pH tumor microenvironment whentargeted by a pH-selective an IL-2Rβ ligand and/or IL-2Rγc ligand. Inthis example, the bioactive moiety is directed to cells located in thelow-pH tumor microenvironment that express the IL-2Rβ subunit and/orIL-2Rγc subunit by the pH-selective IL-2Rβ ligand and/or IL-2Rγc ligand.Thus, the activity of the pH-selective bioactive moiety is enhanced inthe low-pH tumor microenvironment.

Compounds comprising an IL-2Rβ ligand and/or IL-2Rγc ligand can furthercomprise a cytotoxic moiety or cytotoxic molecule. Such compounds can beused to deliver a cytotoxic moiety or compound to a cell expressing theIL-2Rβ subunit and/or IL-2Rγc subunit such as T-cells. The cytotoxicmoiety or molecule can exert cytotoxicity when bound to the compound orcan be cleavable and the moiety or molecule can be cytotoxic whenreleased from the compound; or the cytotoxic moiety can be activated byelectromagnetic radiation.

The cytotoxic moiety or molecule can be used to deplete cells expressingthe IL-2Rβ subunit and/or the IL-2Rγc subunit being targeted.

IL-2Rβ ligand- and/or IL-2Rγc ligand-containing cytotoxic compounds canhave more than one IL-2Rβ ligand and/or more than one IL-2Rγc ligand andthereby can exhibit a higher affinity and/or selectivity to cells,populations of cells, and tissue that highly express the IL-2Rβ subunitand/or the IL-2Rγc subunit compared to cells having a lower expressionlevel of the IL-2Rβ subunit and/or the IL-2Rγc subunit.

IL-2Rβ ligand- and/or IL-2Rγc ligand-containing cytotoxic compounds canfurther include a cell surface targeting component. Such cytotoxiccompounds can exhibit enhanced efficacy to cells, populations of cells,and tissue expressing the IL-2Rβ subunit and/or IL-2Rγc subunit and thesurface target component.

Examples of suitable cytotoxic molecules include anti-microtubuleagents, alkylating agents, and DNA minor groove binding agents.

Compounds comprising an IL-2Rβ ligand and/or IL-2Rγc ligand can furthercomprise a moiety having a useful pharmacological activity unrelated toIL-2 activity.

The pharmacological moiety can function synergistically with IL-2Ragonist activity or synergistically with IL-2R antagonist activity orthe pharmacology moiety may not exhibit synergism with activity of theIL-2Rβ subunit and/or the IL-2Rγc subunit.

Examples of suitable pharmacological moieties include antibodies andantibody fragments that are inhibitors of checkpoint molecules,pro-apototic and anti-apoptotic molecules, cytotoxic molecules, agonistsof chemokine, antagonists of chemokine, cytokine, growth factor andother cell surface receptors, and ligands and inhibitors of cell surfaceadhesion molecules such as integrins.

Peptides provided by the present disclosure can be synthesized bymethods known in the art, for example, by using standard solid phasetechniques.

A peptide comprising an IL-2Rβ ligand and/or IL-2Rγc ligand provided bythe present disclosure can be modified, for example, by phosphorylation,and by other methods known in the art. Thus, the peptides provided bythe disclosure can also serve as a basis to prepare peptide mimeticswith similar biological activity.

A variety of techniques are available for constructing peptide mimeticswith the same or similar desired biological activity as a correspondingpeptide but with more favorable activity than the peptide with respectto solubility, stability, and susceptibility to hydrolysis andproteolysis.

Selective IL-2Rβγc agonists and compounds comprising IL-2Rβ ligandsand/or IL-2Rγc ligands provided by the present disclosure may beincorporated into pharmaceutical compositions to be administered to apatient by any appropriate route of administration includingintradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,intranasal, epidural, oral, peroral, sublingual, intracerebral,intravaginal, transdermal, rectal, inhalation, or topical. In certainembodiments, pharmaceutical compositions provided by the presentdisclosure are injectable formulations. Pharmaceutical compositionsprovided by the present disclosure can be injectable intravenousformulations. Pharmaceutical compositions provided by the presentdisclosure can be oral formulations. Oral formulations may be oraldosage forms. A pharmaceutical composition may be formulated forintravenous administration or for subcutaneous administration.

Pharmaceutical compositions provided by the present disclosure maycomprise a therapeutically-effective amount of a selective IL-2Rβγcagonist, a compound comprising an IL-2Rβ ligand and/or an IL-2Rγcligand, or a pharmaceutically acceptable salt of any of the foregoingtogether with a suitable amount of one or more pharmaceuticallyacceptable vehicles so as to provide a composition for properadministration to a patient. Suitable pharmaceutical vehicles andmethods of preparing pharmaceutical compositions are described in theart.

A selective IL-2Rβγc agonist or a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand may be administered by intravenous injection.Suitable forms for injection include sterile aqueous solutions ordispersions of a selective IL-2Rβγc agonist or compound comprising anIL-2Rβ ligand and/or IL-2Rγc ligand. A selective IL-2Rβγc agonist or acompound comprising an IL-2Rβ ligand and/or IL-2Rγc ligand may beformulated in a physiological buffer solution. Prior to administration,a selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or IL-2Rγc ligand, or a pharmaceutically acceptable salt of any ofthe foregoing may be sterilized by any art recognized the technique,including addition of antibacterial or antifungal agents, for example,paraben, chlorobutanol, phenol, sorbic acid, thimersol, and the like. Aselective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or IL-2Rγc ligand, or a pharmaceutically acceptable salt of any ofthe foregoing may be sterilized by filtration before administration to asubject thereby minimizing or eliminating the need for additionalsterilization agents. An injectable dosage of a selective IL-2Rβγcagonist or a compound comprising an IL-2Rβ ligand and/or IL-2Rγc ligandmay include from about 0.01 mL to about 10 mL, from about 0.1 mL toabout 10 mL, from about 0.1 mL to about 5 mL, and in certainembodiments, from about 1 mL to about 5 mL.

Pharmaceutical compositions may comprise a therapeutically effectiveamount of one or more selective IL-2Rβγc agonists or compoundscomprising an IL-2Rβ ligand and/or IL-2Rγc ligand, preferably inpurified form, together with a suitable amount of a pharmaceuticallyacceptable vehicle, so as to provide a form for proper administration toa patient. When administered to a patient, the compounds andpharmaceutically acceptable vehicles are preferably sterile. Water is apreferred vehicle when the compound is administered intravenously.Saline solutions and aqueous dextrose and glycerol solutions may also beemployed as liquid vehicles, particularly for injectable solutions.Suitable pharmaceutical vehicles also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. Pharmaceutical compositions may also contain minor amounts ofwetting or emulsifying agents, or pH buffering agents. In addition,auxiliary, stabilizing, thickening, lubricating and coloring agents maybe used.

Pharmaceutical compositions comprising a compound may be manufactured bymeans of conventional mixing, dissolving, granulating, levitating,emulsifying, encapsulating, entrapping or lyophilizing processes.Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers, diluents;excipients or auxiliaries, which facilitate processing of compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Pharmaceuticalcompositions provided by the present disclosure may take the form ofsolutions, suspensions, emulsion, or any other form suitable for use.Examples of suitable pharmaceutical vehicles are described in the art.

For parenteral administration, selective IL-2Rβγc agonists and compoundscomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand may be incorporatedinto a solution or suspension. Parenteral administration refers to theadministration by injection, for instance by intravenous, intracapsular,intrathecal, intrapleural, intratumoral, subcutaneously, orintraperitoneal injection or intravesically. A selective IL-2Rβγcagonist or compound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligandcan be administered intravenously.

A solution or suspension may also comprise at least one of the followingadjuvants: sterile diluents such as water for injection, saline, fixedoils, polyethylene glycols, glycerol, propylene glycol or othersynthetic solvents, antioxidants such as ascorbic acid or sodiumbisulfite, buffers such as acetates, citrates or phosphates, and agentsfor adjustment of the tonicity such as sodium chloride or dextrose. Aparenteral preparation may be enclosed into ampoules, disposablesyringes or multiple dosage vessels made of glass or plastic.

Assessing single patient response to therapy and qualifying a patientfor optimal therapy are among the greatest challenges of modernhealthcare and relate to trends in personalized medicine. The selectiveIL-2Rβγc agonist or compound comprising an IL-2Rβ ligand and/or IL-2Rγcligand can have target selectivity for certain cancers. SelectiveIL-2Rβγc agonists and compounds comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand, radiolabeled for positron emission tomography (PET) orSingle Photon Emission Computed Tomography (SPECT) may be used topredict the targeting of the treatment based on a single-study,case-by-case patient analysis thus excluding subjects that are expectednot to benefit from treatment. PET/SPECT scans using radiolabeledselective IL-2Rβγc agonists or compounds comprising an IL-2Rβ ligandand/or IL-2Rγc ligand, once correlated to the concentration selectiveIL-2Rβγc agonist or compound comprising an IL-2Rβ ligand and/or IL-2Rγcligand can provide a three-dimensional distribution map, which can thenbe used for macroscopic dose calculations.

Accordingly, it is within the capability of those of skill in the art toassay and use the selective IL-2Rβγc agonist, a compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand, and/or pharmaceuticalcompositions thereof for therapy.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or IL-2Rγc ligand, and/or pharmaceutical composition thereof cangenerally be used in an amount effective to achieve the intendedpurpose. For use to treat a disease such as cancer, a selective IL-2Rβγcagonist, a compound comprising an IL-2Rβ ligand and/or an IL-2Rγcligand, and/or pharmaceutical compositions thereof, may be administeredor applied in a therapeutically effective amount.

The amount of a selective IL-2Rβγc agonist, a compound comprising anIL-2Rβ ligand and/or IL-2Rγc ligand, and/or pharmaceutical compositionof any of the foregoing that will be effective in the treatment of aparticular disorder or condition disclosed herein will depend in part onthe nature of the disorder or condition, and can be determined bystandard clinical techniques known in the art. In addition, in vitro orin vivo assays may optionally be employed to help identify optimaldosage ranges. The amount of selective IL-2Rβγc agonist, a compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand, and/orpharmaceutical composition of any of the foregoing administered willdepend on, among other factors, the subject being treated, the weight ofthe subject, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician.

A selective IL-2Rβγc agonist or a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand may be assayed in vitro and in vivo, for thedesired therapeutic activity, prior to use in humans. For example, invitro assays may be used to determine whether administration of aspecific compound or a combination of compounds is preferred. Thecompounds may also be demonstrated to be effective and safe using animalmodel systems.

In certain embodiments, a therapeutically effective dose of a selectiveIL-2Rβγc agonist, a compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand, and/or pharmaceutical composition of any of theforegoing will provide therapeutic benefit without causing substantialtoxicity. Toxicity of a selective IL-2Rβγc agonist, a compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand, and/orpharmaceutical compositions of any of the foregoing may be determinedusing standard pharmaceutical procedures and may be readily ascertainedby the skilled artisan. The dose ratio between toxic and therapeuticeffect is the therapeutic index. In certain embodiments, a selectiveIL-2Rβγc agonist, a compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand, and/or pharmaceutical composition of any of theforegoing exhibits a particularly high therapeutic index in treatingdisease and disorders. A dose of a selective IL-2Rβγc agonist a compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand, and/orpharmaceutical composition of any of the foregoing will be within arange of circulating concentrations that include an effective dose withminimal toxicity.

A compound comprising an IL-2Rβ and/or an IL-2Rγc ligand provided by thepresent disclosure or a pharmaceutical composition thereof may beincluded in a kit that may be used to administer the compound to apatient for therapeutic purposes. A kit may include a pharmaceuticalcomposition comprising a selective IL-2Rβγc agonist or a compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand provided by thepresent disclosure suitable for administration to a patient andinstructions for administering the pharmaceutical composition to thepatient. The kit can be a kit for treating cancer. A kit for use intreating cancer in a patient can comprise a selective IL-2Rβγc agonistor a compound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligandprovided by the present disclosure, a pharmaceutically acceptablevehicle for administering the compound, and instructions foradministering the compound to a patient.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

Instructions supplied with a kit may be printed and/or supplied, forexample, as an electronic-readable medium, a video cassette, anaudiotape, a flash memory device, or may be published on an internet website or distributed to a patient and/or health care provider as anelectronic communication.

Selective IL-2Rβγc agonists and compounds comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand provided by the present disclosure may be usedfor treating cancer in a patient. The cancer can be, for example, asolid tumor or a metastasis.

Selective IL-2Rβγc agonists and compounds comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand provided by the present disclosure or apharmaceutical composition thereof may be administered to treat a cancerknown to be treated by activation or inhibition of the IL-2 receptor.Selective IL-2Rβγc agonists and compounds comprising an IL-2Rβ ligandand/or IL-2Rγc ligand provided by the present disclosure or apharmaceutical composition thereof may be administered to treat a cancerknown to be treated by activation or inhibition of the IL-2Rβγc subunitsand where simultaneous activation of the IL-2Rα subunit compromisestherapeutic efficacy and/or minimizes unwanted side effects.

Selective IL-2Rβγc agonists and compounds comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand provided by the present disclosure or apharmaceutical composition thereof can be used to treat, for example,one or more of the following cancers: acute lymphoblastic leukemia,acute myeloid leukemia, adrenocortical carcinoma, appendix cancer,astrocytoma, atypical teratoid/rhabdoid tumor, basal cell carcinoma(nonmelanoma), B-cell lymphoma, bladder cancer, bone cancer, brain andspinal cord tumors, brain stem cancer, brain tumor, breast cancer,bronchial tumors, Burkitt lymphoma, carcinoid tumor, carcinoma of headand neck, central nervous system embryonal tumors, cerebellarastrocytoma, cerebral astrocytoma/malignant glioma, cervical cancer,chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia,colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,desmoplastic small round cell tumor, ductal carcinoma, dye cancer,endocrine pancreas tumors (islet cell tumors), endometrial cancer,ependymoblastoma, esophageal cancer, esthesioneuroblastoma, Ewing familyof tumors, extracranial germ cell tumor, extrahepatic bile duct cancer,gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor, gestational trophoblastic tumor,glioblastoma, glioma, hairy cell leukemia, head and neck cancer, heartcancer, hematopoetic tumors of the lymphoid lineage, hepatocellularcancer, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic and visualpathway glioma, IDs-related lymphoma, intraocular melanoma, islet celltumors, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis,laryngeal cancer, leukemia, lip and oral cavity cancer, male breastcancer, malignant fibrous histiocytoma, malignant germ cell tumors,malignant mesothelioma, medulloblastoma, melanoma, Merkel cellcarcinoma, mesothelioma, mouth cancer, multiple endocrine neoplasiasyndrome, multiple myeloma, mycosis fungoides, myelodysplastic,myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer,nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-smallcell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma,ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor,ovarian low malignant potential tumor, pancreatic cancer, pancreaticneuroendocrine tumors (islet cell tumors), papillomatosis,paraganglioma, paranasal sinus and nasal cavity cancer, parathyroidcancer, penile cancer, pharyngeal cancer, pheochromocytoma, pinealparenchymal tumors, pineoblastoma and supratentorial primitiveneuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiplemyeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primarycentral nervous system lymphoma, primary liver cancer, primarymetastatic squamous neck cancer with occult, prostate cancer, rectalcancer, renal cell cancer, renal pelvis and ureter, respiratory tractcarcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer,sarcoma, Sdzary syndrome, skin cancer, skin cancer, small intestinecancer, soft tissue sarcoma, squamous cell carcinoma (nonmelanoma),stomach cancer, supratentorial primitive neuroectodermal tumors, T-celllymphoma, testicular cancer, throat cancer, thymoma and thymiccarcinoma, thyroid cancer, transitional cell cancer, urethral cancer,uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma,vulvar cancer, Waldenström macroglobulinemia, Wilms tumor, and systemicand central metastases of any of the foregoing.

Selective IL-2Rβγc agonists and compounds comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand provided by the present disclosure, or apharmaceutical composition of any of the foregoing can be used to treatsolid tumors.

Selective IL-2Rβγc agonists, compounds comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand provided by the present disclosure or apharmaceutical composition of any of the foregoing can be used to treat,for example, one or more of the following cancers wherein the cancer isselected from any of the primary adult and childhood brain and CNScancers including glioblastoma (GBM) and astrocytoma, skin cancersincluding melanoma, lung cancers including small cell lung cancers,non-small cell lung cancers (NSCLC), and large cell lung cancers,breasts cancers including triple negative breast cancer (TNBC), bloodcancers including myelodysplastic syndrome (MDS), multiple myeloma (MM),and acute myeloid leukemia (AML), prostate cancer including castrateresistant prostate cancer (CRPC), liver cancers including hepatocellularcarcinoma (HCC), esophageal and gastric cancers, and any systemic andcentral metastases of any of the foregoing.

The amount of a selective IL-2Rβγc agonists, compounds comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand provided by the presentdisclosure, or pharmaceutical composition of any of the foregoing thatwill be effective in the treatment of a cancer will depend, at least inpart, on the nature of the disease, and may be determined by standardclinical techniques known in the art. In addition, in vitro or in vivoassays may be employed to help identify optimal dosing ranges. Dosingregimens and dosing intervals may also be determined by methods known tothose skilled in the art. The amount of a selective IL-2Rβγc agonist orcompound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand providedby the present disclosure administered may depend on, among otherfactors, the subject being treated, the weight of the subject, theseverity of the disease, the route of administration, and the judgmentof the prescribing physician.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. Initial doses may also beestimated from in vivo data, e.g., animal models, using techniques thatare known in the art. Such information may be used to more accuratelydetermine useful doses in humans. One having ordinary skill in the artmay optimize administration to humans based on animal data.

A dose of a selective IL-2Rβγc agonist or compound comprising an IL-2Rβligand and/or an IL-2Rγc ligand provided by the present disclosure andappropriate dosing intervals may be selected to maintain a sustainedtherapeutically effective concentration of the selective IL-2Rβγcagonist or compound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligandprovided by the present disclosure in the blood of a patient, and incertain embodiments, without exceeding a minimum adverse concentration.

In certain embodiments, pharmaceutical compositions comprising aselective IL-2Rβγc agonist or compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand provided by the present disclosure may beadministered, for example once per week, every 2 weeks, every 3 weeks,every 4 weeks, every 5 weeks, or every 6 weeks. Dosing may be providedalone or in combination with other drugs and may continue as long asrequired for effective treatment of the disease. Dosing may also beundertaken using continuous or semi-continuous administration over aperiod of time. Dosing includes administering a pharmaceuticalcomposition to a mammal, such as a human, in a fed or fasted state.

A pharmaceutical composition may be administered in a single dosage formor in multiple dosage forms or as a continuous or an accumulated doseover a period of time. When multiple dosage forms are used the amount ofa selective IL-2Rβγc agonist or compound comprising an IL-2Rβ ligandand/or IL-2Rγc ligand provided by the present disclosure containedwithin each of the multiple dosage forms may be the same or different.

Suitable daily dosage ranges for administration may range from about 2μg to about 200 mg of a selective IL-2Rβγc agonist or compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand provided by thepresent disclosure per kilogram body weight.

Suitable daily dosage ranges for administration may range from about 1μg to about 50 mg of a selective IL-2Rβγc agonist or compound comprisingan IL-2Rβ ligand and/or an IL-2Rγc ligand provided by the presentdisclosure per square meter (m²) of body surface.

A selective IL-2Rβγc agonist or compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand provided by the present disclosure may beadministered to treat cancer in a subject in an amount, for example,from 0.001 mg/day to 100 mg/day, or in any other appropriate daily dose.A dose can be for example, from 0.01 μg/kg body weight/week to 100 μg/kgbody weight/week or any other suitable dose.

A pharmaceutical composition comprising a selective IL-2Rβγc agonist orcompound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand providedby the present disclosure may be administered to treat cancer in asubject so as to provide a therapeutically effective concentration of aselective IL-2Rβγc agonist or compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand provided by the present disclosure in the bloodor plasma of the subject. A therapeutically effective concentration of acompound of a selective IL-2Rβγc agonist or compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand provided by the presentdisclosure in the blood of a subject can be, for example, from 0.01 μg/Lto 1,000 μg/L, from 0.1 μg/L to 500 μg/L, from 1 μg/L to 250 μg/L, orfrom about 10 μg/L to about 100 μg/L. A therapeutically effectiveconcentration of a selective IL-2Rβγc agonist or compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand provided by the presentdisclosure in the blood of a subject can be, for example, at least 0.01μg/L, at least 0.1 μg/L, at least 1 μg/L, at least about 10 pg/L, or atleast 100 pg/L. A therapeutically effective concentration of a selectiveIL-2Rβγc agonist or compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand in the blood of a subject can be, for example, less thanan amount that causes unacceptable adverse effects including adverseeffects to homeostasis. A therapeutically effective concentration of aselective IL-2Rβγc agonist or compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand in the blood of a subject can be an amountsufficient to restore and/or maintain homeostasis in the subject.

Pharmaceutical compositions comprising a selective IL-2Rβγc agonist orcompound comprising an IL-2Rβ ligand and/or IL-2Rγc ligand may beadministered to treat a disease in a subject so as to provide atherapeutically effective concentration of the selective IL-2Rβγcagonist or compound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligandin the blood of a subject for an extended period of time such as, forexample, for at least about 4 hours, for at least about 6 hours, for atleast about 12 hours, for at least 1 day, for at least 2 days, for atleast 3 days, or at least 1 week.

The amount of a selective IL-2Rβγc agonist or compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand administered may vary during atreatment regimen.

Pharmaceutical compositions provided by the present disclosure mayfurther comprise one or more pharmaceutically active compounds inaddition to a selective IL-2Rβγc agonist or compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand provided by the presentdisclosure. Such compounds may be provided, for example, to treat thecancer being treated with the a selective IL-2Rβγc agonist a compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand or to treat adisease, disorder, or condition other than the cancer being treated withthe selective IL-2Rβγc agonist or compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, to treat a side-effect caused by administeringthe selective IL-2Rβγc agonist or compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, to augment the efficacy of the a selectiveIL-2Rβγc agonist or compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand, and/or to modulate the activity of the selectiveIL-2Rβγc agonist or compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand.

A selective IL-2Rβγc agonist or compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand provided by the present disclosure may be usedin combination with at least one other therapeutic agent. A selectiveIL-2Rβγc agonist or compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand may be administered to a patient together with anothercompound for treating cancer in the subject. In certain embodiments, theat least one other therapeutic agent may be a different selectiveIL-2Rβγc agonist or compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand. A selective IL-2Rβγc agonist or compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand and the at least one othertherapeutic agent may act additively or, and in certain embodiments,synergistically. The at least one additional therapeutic agent may beincluded in the same pharmaceutical composition or vehicle comprisingthe selective IL-2Rβγc agonist or compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand or may be in a separate pharmaceuticalcomposition or vehicle. Accordingly, methods provided by the presentdisclosure further include, in addition to administering a selectiveIL-2Rβγc agonist or compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand, administering one or more therapeutic agents effectivefor treating cancer or a different disease, disorder or condition thancancer. Methods provided by the present disclosure includeadministration of a selective IL-2Rβγc agonist or compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand and one or more other therapeuticagents provided that the combined administration does not inhibit thetherapeutic efficacy of a selective IL-2Rβγc agonist or compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand and/or does notproduce adverse combination effects.

A pharmaceutical composition comprising a selective IL-2Rβγc agonist ora compound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand may beadministered concurrently with the administration of another therapeuticagent, which may be part of the same pharmaceutical composition as, orin a different pharmaceutical composition than that comprising aselective IL-2Rβγc agonist and/or a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand. A selective IL-2Rβγc agonist and/or a compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand may be administeredprior or subsequent to administration of another therapeutic agent. Incertain embodiments of combination therapy, the combination therapy maycomprise alternating between administering a selective IL-2Rβγc agonistor a compound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand and acomposition comprising another therapeutic agent, e.g., to minimizeadverse drug effects associated with a particular drug. When a selectiveIL-2Rβγc agonist or a compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand is administered concurrently with another therapeuticagent that potentially may produce an adverse drug effect including, forexample, toxicity, the other therapeutic agent may be administered at adose that falls below the threshold at which the adverse drug reactionis elicited.

A pharmaceutical composition comprising a selective IL-2Rβγc agonist ora compound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand providedby the present disclosure may be administered with one or moresubstances, for example, to enhance, modulate and/or control release,bioavailability, therapeutic efficacy, therapeutic potency, and/orstability, of the selective IL-2Rβγc agonist or compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand. For example, a pharmaceuticalcomposition comprising a selective IL-2Rβγc agonist or compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand can beco-administered with an active agent having pharmacological effects thatenhance the therapeutic efficacy of the selective IL-2Rβγc agonist orcompound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with an agent knownor believed to be effective in treating cancer in a patient, such as thesame cancer being treated with the selective IL-2Rβγc agonist orcompound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with an agent knownor believed to interfere with proliferation.

In certain embodiments, a selective IL-2Rβγc agonist, a compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand, or apharmaceutical composition comprising any of the foregoing may beadministered in conjunction with an agent known or believed to interferewith metabolism. A selective IL-2Rβγc agonist, a compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand, or a pharmaceutical compositioncomprising any of the foregoing may be administered in conjunction withan agent known or believed to interfere with mitochondrial metabolism. Aselective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with an agent knownor believed to be an anti-metabolite. A selective IL-2Rβγc agonist, acompound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand, or apharmaceutical composition comprising any of the foregoing may beadministered in conjunction with an agent known or believed to interfereRNA transcription. A selective IL-2Rβγc agonist, a compound comprisingan IL-2Rβ ligand and/or an IL-2Rγc ligand, or a pharmaceuticalcomposition comprising a selective IL-2Rβγc agonist may be administeredin conjunction with an agent known or believed to interfere with RNAtranslation. A selective IL-2Rβγc agonist, a compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand, or a pharmaceutical compositioncomprising any of the foregoing may be administered in conjunction withan agent known or believed to interfere with protein synthesis. Aselective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with an agent knownor believed to interfere with synthesis of precursors for DNA synthesisand replication. A selective IL-2Rβγc agonist, a compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand, or a pharmaceutical compositioncomprising any of the foregoing may be administered in conjunction withan agent known or believed to interfere with purine synthesis. Aselective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with an agent knownor believed to interfere with nucleoside synthesis. A selective IL-2Rβγcagonist, a compound comprising an IL-2Rβ ligand and/or an IL-2Rγcligand, or a pharmaceutical composition of any of the foregoing may beadministered in conjunction with an agent known or believed to interactwith mTOR. A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβligand and/or an IL-2Rγc ligand, or a pharmaceutical composition of anyof the foregoing may be administered in conjunction with an agent knownor believed to interact be an mTOR inhibitor. A selective IL-2Rβγcagonist, a compound comprising an IL-2Rβ ligand and/or an IL-2Rγcligand, or a pharmaceutical composition of any of the foregoing may beadministered in conjunction with an agent known or believed to interferewith cell cycle checkpoints.

An IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand, or a pharmaceutical composition of any of the foregoingmay be administered in conjunction with a checkpoint inhibitor includingCTLA-4 inhibitors such as ipilimumab, PD1 inhibitors such aspembrolizumab and nivolumab, and PD-LI inhibitors such as atezolizumab,avelumab, and durvalumab. An IL-2Rβγc agonist, a compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand, or a pharmaceutical compositionof any of the foregoing may be administered in conjunction with animmunomodulator such as CD137/4-1BB, CD27, GIYR, and/or OC40.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition of any of theforegoing may be administered in conjunction with an agent known orbelieved to be cytotoxic. A selective IL-2Rβγc agonist, a compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand, or apharmaceutical composition of any of the foregoing may be administeredin conjunction with an agent known or believed to be cytostatic. Aselective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition of any of theforegoing may be administered in conjunction with an agent known orbelieved to cause DNA damage. A selective IL-2Rβγc agonist, a compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand, or apharmaceutical composition of any of the foregoing may be administeredin conjunction with an agent known or believed to cause cell cyclearrest. A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβligand and/or an IL-2Rγc ligand, or a pharmaceutical compositioncomprising of any of the foregoing may be administered in conjunctionwith an agent known or believed to cause mitotic catastrophe.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition of any of theforegoing may be administered in conjunction with an agent known orbelieved to modulate drug resistance. A selective IL-2Rβγc agonist, acompound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand, or apharmaceutical composition of any of the foregoing may be administeredin conjunction with an agent known or believed to reduce multi-drugresistance. A selective IL-2Rβγc agonist, a compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand, or a pharmaceutical compositionof any of the foregoing may be administered in conjunction with an agentknown or believed to interact with membrane proteins. A selectiveIL-2Rβγc agonist, a compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand, or a pharmaceutical composition comprising any of theforegoing may be administered in conjunction with an agent known orbelieved to interact with plasma membrane proteins. A selective IL-2Rβγcagonist, a compound comprising an IL-2Rβ ligand and/or an IL-2Rγcligand, or a pharmaceutical composition comprising any of the foregoingmay be administered in conjunction with an agent known or believed tointeract with nuclear membrane proteins. A selective IL-2Rβγc agonist, acompound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand, or apharmaceutical composition comprising any of the foregoing may beadministered in conjunction with an agent known or believed to interactwith a major vault protein or proteins. A selective IL-2Rβγc agonist, acompound comprising an IL-2Rβ ligand and/or an IL-2Rγc ligand, or apharmaceutical composition comprising any of the foregoing may beadministered in conjunction with an agent known or believed to interactwith gen products of the MVP (major vault protein) gene.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition of any of theforegoing, may be administered in conjunction with an agent known orbelieved to modulate glutathione concentration. A selective IL-2Rβγcagonist, a compound comprising an IL-2Rβ ligand and/or an IL-2Rγcligand, or a pharmaceutical composition comprising any of the foregoingmay be administered in conjunction with an agent known or believed tomodulate glutathione concentration within cells. A selective IL-2Rβγcagonist, a compound comprising an IL-2Rβ ligand and/or an IL-2Rγcligand, or a pharmaceutical composition comprising a selective IL-2Rβγcagonist or a compound comprising an IL-2Rβ ligand and/or an IL-2Rγcligand may be administered in conjunction with an agent known orbelieved to decrease glutathione concentration within cells. A selectiveIL-2Rβγc agonist, a compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand, or a pharmaceutical composition comprising a selectiveIL-2Rβγc agonist or a compound comprising an IL-2Rβ ligand and/orIL-2Rγc ligand may be administered in conjunction with an agent known orbelieved to reduce glutathione uptake into cells. A selective IL-2Rβγcagonist, a compound comprising an IL-2Rβ ligand and/or an IL-2Rγcligand, or a pharmaceutical composition comprising any of the foregoingmay be administered in conjunction with an agent known or believed toreduce glutathione synthesis. A selective IL-2Rβγc agonist, a compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand, or apharmaceutical composition comprising any of the foregoing may beadministered in conjunction with an agent known or believed to reduceglutathione synthesis within cells.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with an agent knownor believed to interfere with neovascularization. A selective IL-2Rβγcagonist, a compound comprising an IL-2Rβ ligand and/or IL-2Rγc ligand,or a pharmaceutical composition comprising any of the foregoing may beadministered in conjunction with an agent known or believed to reduceneovascularization. A selective IL-2Rβγc agonist, a compound comprisingan IL-2Rβ ligand and/or an IL-2Rγc ligand, or a pharmaceuticalcomposition comprising any of the foregoing may be administered inconjunction with an agent known or believed to promoteneovascularization.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with an agent knownor believed to interfere with hormone homeostasis. In certainembodiments, a selective IL-2Rβγc agonist, a compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand, or a pharmaceutical compositioncomprising any of the foregoing may be administered in conjunction withan agent known or believed to interfere with hormone synthesis. Aselective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or IL-2Rβ ligand and/or an IL-2Rγc ligand or a pharmaceuticalcomposition comprising any of the foregoing may be administered inconjunction with an agent known or believed to interfere with hormonereceptor binding. A selective IL-2Rβγc agonist, a compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand, or a pharmaceutical compositioncomprising any of the foregoing may be administered in conjunction withan agent known or believed to interfere with hormone signaltransduction.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with an agent knownor believed to interfere with growth factor homeostasis. A selectiveIL-2Rβγc agonist, a compound comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand, or a pharmaceutical composition comprising any of theforegoing may be administered in conjunction with an agent known orbelieved to interfere with growth factor synthesis. A selective IL-2Rβγcagonist, a compound comprising an IL-2Rβ ligand and/or an IL-2Rγcligand, or a pharmaceutical composition comprising any of the foregoingmay be administered in conjunction with an agent known or believed tointerfere with growth factor receptor expression. A selective IL-2Rβγcagonist, a compound comprising an IL-2Rβ ligand and/or an IL-2Rγcligand, or a pharmaceutical composition comprising any of the foregoingmay be administered in conjunction with an agent known or believed tointerfere with growth factor binding to growth factor receptors. Aselective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with an agent knownor believed to interfere with growth factors binding to growth factorreceptors. A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβligand and/or an IL-2Rγc ligand, or a pharmaceutical compositioncomprising any of the foregoing may be administered in conjunction withan agent known or believed to interfere with growth factor receptorsignal transduction. A selective IL-2Rβγc agonist, a compound comprisingan IL-2Rβ ligand and/or IL-2Rγc ligand, or a pharmaceutical compositioncomprising any of the foregoing may be administered in conjunction withan agent known or believed to interfere with the Hedgehog (Hh)signaling. A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβligand and/or an IL-2Rγc ligand, or a pharmaceutical compositioncomprising any of the foregoing may be administered in conjunction withan agent known or believed to inhibit the Hedgehog pathway signaling. Aselective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with an agent knownor believed to inhibit ALK (anaplastic lymphoma kinase) pathwaysignaling. A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβligand and/or an IL-2Rγc ligand, or a pharmaceutical compositioncomprising any of the foregoing may be administered in conjunction withan agent known or believed to inhibit non-homologous end joining (NHEJ)is a pathway.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition of any of theforegoing may be administered in conjunction with one or more agentsknown or believed to be a VEGFR (vascular endothelial growth factorreceptor) inhibitor, a RTK (receptor tyrosine kinase) inhibitor, asodium channel current blocker, aFAK (focal adhesion kinase) inhibitor,a GLI (glioma-associated oncogene) inhibitor, a GLI1 inhibitor, a GLI2inhibitor, a GLI3 inhibitor, a MAPK (mitogen-activated protein kinase)inhibitor, a MAPK/ERK pathway (also known as Ras-Raf-MEK-ERK pathways)inhibitor, a MEK1 inhibitor, a MEK2 inhibitor, a MEK5 inhibitor, aMEK5/ERK5 inhibitor, aRTA (renal tubular acidosis) inhibitor, a ALK(anaplastic lymphoma kinase) inhibitor, Aa LK kinase inhibitor, anuclear translocation inhibitor, a PORCN (porcupine) inhibitor, a 5-ARI(5α-reductase inhibitor), topoisomerase inhibitor, a Ras (rat sarcoma)inhibitor, a K-ras inhibitor, a CERK (ceramide kinase) inhibitor, a PKB(protein kinase B, also known as AKT) inhibitor, a AKT1 inhibitor, EZH2(enhancer of zeste homolog 2) inhibitor, a BET (bromodomain and extraterminal domain motif) inhibitor, a SYK (apleen tyrosine kinase)inhibitor, JAK (janus kinase) inhibitors, a SYK/JAK inhibitor, a IDO(indoleamine-pyrrole 2,3-dioxygenase) inhibitor, a IDO1 inhibitor, a RXR(retinoic X receptors) activating agent, a selectively RXR activatingagent, a p-glycoprotein inhibitor, a ERK inhibitor, a PI3K(phosphatidylinositol-4,5-bisphosphate 3-kinase) inhibitor, a BRD(bromodomain-containing protein) inhibitor, a BRD2 inhibitor, a BRD3inhibitor, a BRD4 inhibitor, a BRDT (bromodomain testis-specificprotein) inhibitor, a reverse transcriptase inhibitor, a NRT (nucleosideanalog reverse-transcriptase) inhibitor, a PIM (proviral integrations ofmoloney virus) inhibitor, a EGFR (epidermal growth factor receptor)inhibitor, a photosensitizer, a radiosensitizer, a ROS (proto-oncogene,receptor tyrosine kinase) inhibitor, a ROS1 (proto-oncogene 1)inhibitor, a CK (caseine kinase) inhibitor, a CK2 inhibitor, a Bcr-Abl(breakpoint cluster region—Abelson proto-oncogene) tyrosine-kinaseinhibitor such as dasatinib, a microtubule stabilizing agent, amicrotubule depolymerization/disassembly inhibitor, a DNA intercalator,an androgen receptor antagonist, a chemoprotective agents, a HDAC(histone deacetylase) inhibitor, a DPP (dipeptidyl pepdidase) inhibitor,a DPP-4 inhibitor, BTK (Bruton's tyrosine kinase) inhibitor, a kinaseinhibitor such as imatinib, a tyrosine kinase inhibitor such asnilotinib, a ARP (poly (ADP-ribose) polymerase) inhibitor, a CDK(cyclin-dependent kinase) inhibitor, a CDK4 inhibitor, a CDK6 inhibitor,a CDK4/6 inhibitor, a HIF1α (hypoxia-inducible factor 1-α) inhibitor, aDNA ligase inhibitor, a DNA ligase IV inhibitor, a NHEJ (non-homologousend joining) inhibitor, a DNA ligase IV, a NHEJ inhibitor and a RAFinhibitor, a TKI and a RAF inhibitor, a TKI and RAF inhibitor such assorafenib, a PDT (photodynamic therapy) sensitizer, an ATR (ataxiatelangiectasia- and Rad3-related protein kinase) inhibitor, or acombination of any of the foregoing.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand or a pharmaceutical composition of any of anyof the foregoing may be administered in conjunction with one or morechemotherapeutic agents, such as, for example, a VEGFR inhibitor such asfruquintinib, motesanib/AMG-706, vatalanib; a RTK inhibitor such asponatinib; a sodium channel blocker such as GS967; a FAK inhibitor suchas TAE226; a GLI1 and GLI2 inhibitor such as GANT61, a MEK inhibitorsuch as binimetinib; a RTA inhibitor such as linifanib; an ALK inhibitorsuch as brigstinib; bromopyruvic acid; a DNA alkylating agent such asthiotepa; nuclear translocations factors such as JSH-23; a PORCninhibitor such as Wnt-C59; a 5α-reductase inhibitor such as dutasteride;a topoisomerase inhibitor such as carubicin; a RAS inhibitor such asKobe0065; a CerK inhibitor such as NVP-231; an AKT inhibitor such asuprosertib; a EZH2 inhibitor such as GSK-503; a BET bromodomaininhibitor such as OTX015; a MEK5/ERK5 inhibitor such as BIX02189; aSyl/JAK inhibitor such as cerdulatinib; an IDO1 inhibitor such asNLG919; a retinoic X receptor activating agent such as bexsrotene; a PGPinhibitor such as acotiamide or actotiamide HCl; an Erk inhibitor suchSCH772984; a PI3K inhibitor such as gedatolisib; a JAK inhibitor such asruxolitinib; an AKT inhibitor such as afuresertib or afuresertib HCl; anALK1 inhibitor such as ceritinib; an HDAC inhibitor such as abexinostat;a DPP inhibitor such as oamarigliptin; an EGFR inhibitor such asgefittinib; an EZH2 inhibitor such as GSK126; a BTK inhibitor such asibrutinib; a kinase inhibitor such as imatinin HCl; an IDO inhibitorsuch as INCB024360; a DNA crosslinker such as mitomycin C; a tyrosinekinase inhibitor such as nilotinib, a PARP inhibitor such as olaparib; atubilin stabilization promoter such as paclitaxel; a CDK4/6 inhibitorsuch as palbociclib; a RTK inhibitor such as sunitinib; a PDT sensitizersuch as tslsporfin; a p-glycoprotein inhibitor such as tariquidar; anATR inhibitor such as VE-822; an HDAC inhibitor such as PCI-24781; a DPPinhibitor such as omarigliptin; an EGFR inhibitor such as gefinib; anEZH2 inhibitor such as GSK126; a BTK inhibitor such as irbrutinib; anIDO inhibitor such as INCB024360; or a combination of any of theforegoing.

For example, a selective IL-2Rβγc agonist, a compound comprising anIL-2Rβ ligand and/or an IL-2Rγc ligand, or a of any of the foregoing maybe administered in conjunction with another chemotherapeutic agents,such as, for example, N-acetyl cysteine (NAC), adriamycin, alemtuzumab,amifostine, arsenic trioxide, ascorbic acid, bendamustine, bevacizumab,bortezomib, busulfan, buthionine sulfoxime, carfilzomib, carmustine,clofarabine, cyclophosphamide, cyclosporine, cytarabine, dasatinib,datinomycin, defibrotide, dexamethasone, docetaxel, doxorubicin,etoposide, filgrastim, floxuridine, fludarabine, gemcitabine, interferonα, ipilimumab, lenalidomide, leucovorin, melphalan, mycofenolatemofetil, paclitaxel, palifermin, panobinostat, pegfilrastim,prednisolone, prednisone, revlimid, rituximab, sirolimus, sodium2-mercaptoethane sulfonate (MESNA), sodium thiosulfate, tacrolimus,temozolomide, thalidomide, thioguanine, thiotepa, topotecan, velcade, ora combination of any of the foregoing. In certain embodiments, aselective IL-2Rβγc agonist and/or pharmaceutical compositions thereofcan be used in combination therapy with other chemotherapeutic agentsincluding one or more antimetabolites such as folic acid analogs;pyrimidine analogs such as fluorouracil, floxuridine, and cytosinearabinoside; purine analogs such as mercaptopurine, thiogunaine, andpentostatin; natural products such as vinblastine, vincristine,etoposide, tertiposide, dactinomycin, daunorubicin, doxurubicin,bleomycin, mithamycin, mitomycin C, L-asparaginase, and interferon α;platinum coordination complexes such as cis-platinum, and carboplatin;mitoxantrone; hydroxyurea; procarbazine; hormones and antagonists suchas prednisone, hydroxyprogesterone caproate, medroxyprogesteroneacetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol,tamoxifen, testosterone propionate, fluoxymesterone, flutamide, andleuprolide, anti-angiogenesis agents or inhibitors such as angiostatin,retinoic acids, paclitaxel, estradiol derivatives, andthiazolopyrimidine derivatives; apoptosis prevention agents; triptolide;colchicine; luliconazole; and radiation therapy.

A selective IL-2Rβγc agonist or a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand may be co-administered with a compound thatinhibits DNA repair such as, for example, 06-benzylguanine (06-BG).

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with one or morechemotherapeutic agents, such as, for example, abarelix, abiraterone,abiraterone acetate, n-acetyl cysteine, aclanibicin hydrochloride,adriamycin, adenine, afatinib, afatinib dimaleate, alemtuzumab,alendronate sodium, alitretinoin, allopurinol sodium, altretamine,amifostine, aminoglutethimide, aminolevulinic acid, amrubicin,amsacrine, anastrozole, angiostatin, apremilast, aprepitant, arsenictrioxide, ascorbic acid, 1-asparaginase, azacitidine, azathioprinesodium, bazedoxifene (serm), belinostat, bendamustine hcl,o6-benzylguanine (o6-bg), bevacizumab, bexarotene, bicalutamide,biricodar, bleomycin sulfate, bortezomib, bosutinib, brivudine,buserelin, busulfan, buthionine sulfoxime, cabazitaxel, cabozantinib,capecitabine, carboplatin, carboquone, carfilzomib, carmofur,carmustine, ceritinib, chlorambucil, cisplatin, cladribine, clodronatedisodium, clofarabine, crizotinib, cyclophosphamide, cyclosporine,cytarabine, cytosine arabinoside, dabrafenib, dacarbazine, dactinomycin,dasatinib, datinomycin, daunorubicin, decitabine, defribrotide,degarelix acetate, dexamethasone, dexrazoxane hydrochloride, diaziquone,diethyl stilbestrol, docetaxel, doxifluridine, doxorubicinhydrochloride, doxorubicin free base, dromostanolone propionate,dutasteride, eltrombopag, enzalutamide, epirubicin hydrochloride,eribulin mesylate, erlotinib hydrochloride, estramustine phosphatesodium, ethinyl estradiol, etoposide phosphate, etoposide, everolimus,exemestane, fentanyl, filgrastim, fingolimod, floxuridine, fludarabinephosphate, fluorouracil, fluoxymesterone, flutamide, formestane,formylmelphalan, fosaprepitant, fotemustine, fulvestrant, gefitinib,gemcitabine hydrochloride, gemcitabine free base, glutathione,glyciphosphoramide, glyfosfin, goserelin acetate, granisetronhydrochloride, heptaplatin, hexyl 5-aminolevulinate, histrelin acetate,hydroxyprogesterone caproate, hydroxyurea, ibandronate sodium,ibrutinib, icotinib, idanibicin HCl, idelalisib, idoxuridine,ifosfamide, interferon α, imatinib mesylate, imiquimod, ingenolmebutate, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotideacetate, lapatinib free base, lapatinib ditosylate, lasofoxifene,lenalidomide, letrozole, leucovorin calcium, leuprolide acetate,levamisole hydrochloride, levoleucovorin calcium, iobenguane,lobaplatin, lomustine, maropitant, masoprocol, mechlorethaminehydrochloride, megestrol acetate, medroxyprogesterone acetate, melphalanhydrochloride, mercaptopurine, mercaptoethane sulfonate sodium,methotrexate, methoxsalen, methyl aminolevulinate, methylene blue,methylisoindigotin, mifamurtide, miltefosine, miriplatin, mithamycin,mitobronitol, mitomycin C, mitotane, mitoxantrone hydrochloride,mycophenolate mofetil, nabiximols, nafarelin, nandrolone, nedaplatin,nelarabine, netupitant, nilotinib, nilutamide, nimustine, nintedanib,nocodazole, octreotide, olaparib, omacetaxine mepesuccinate, ondansetronhydrochloride, oxaliplatin, paclitaxel, palbociclib, palifermin,palonosetron hydrochloride, pamidronate disodium, panobinostat,pasireotide, pazopanib hydrochloride, pegfilrastim, pemetrexed disodium,pentostatin, peplomycin, pipobroman, pirarubicin, plerixafor,plicamycin, pomalidomide, ponatinib, porfimer sodium, porfiromycin,pralatrexate, prednimustine, prednisolone, prednisone, procarbazinehydrochloride, quinagolide hydrochloride, raloxifene, raltitrexed,radotinib, ranimustine, retinoic acids, revlimide, rituxinab,romidepsin, ruxolitinib, ruxolitinib phosphate, semustine, sirolimus,sodium thiosulfate, sorafenib free base, sorafenib tosylate,streptozocin, sufentanil, sunitinib, tacrolimus, talaporfin sodium,tamibarotene, tamoxifen citrate, tapentadol, temoporfin, temozolomide,temsirolimus, teniposide, teriflunomide, tertiposide, testolactone,testosterone propionate, thalidomide, thioguanine, thiotepa,thymalfasin, toceranib phosphate, topotecan hydrochloride, toremifenecitrate, trabectedin, trametinib, tretinoin, trilostane, triptorelin,tropisetron, uramustine, valrubicin, vandetanib, vedotin, vemurafenib,verteporfin, vinblastine, vincristine sulfate, vincristine free base,vindesine, vinorelbine tartrate, vorinostat, and zoledronic acid.

A selective IL-2Rβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with one or morechemotherapeutic agents, including abemaciclib, abiraterone acetate,ABVD, ABVE, ABVE-PC, AC, acalabrutinib, AC-T, ADE, ado-trastuzumabemtansine, afatinib dimaleate, aldesleukin, alectinib, alemtuzumab,alpelisib, amifostine, aminolevulinic acid hydrochloride, anastrozole,apalutamide, aprepitant, arsenic trioxide, asparaginase Erwiniachrysanthemi, atezolizumab, avelumab, axicabtagene ciloleucel, axitinib,azacitidine, BEACOPP, belinostat, bendamustine hydrochloride, BEP,bevacizumab, bexarotene, bicalutamide, binimetinib, bleomycin sulfate,blinatumomab, bortezomib, bosutinib, brentuximab vedotin, brigatinib,BuMel, busulfan, cabazitaxel, cabozantinib-s-malate, CAF, calaspargasepegol-mknl, capecitabine, caplacizumab-yhdp, CAPOX, carboplatin,carboplatin-taxol, carfilzomib, carmustine, carmustine implant, CEM,cemiplimab-rwlc, ceritinib, cetuximab, CEV, chlorambucil,chlorambucil-prednisone, CHOP, cisplatin, cladribine, clofarabine, CMF,cobimetinib, copanlisib hydrochloride, COPDAC, COPP, COPP-ABV,crizotinib, CVP, cyclophosphamide, cytarabine, cytarabine liposome,dabrafenib mesylate, dacarbazine, dacomitinib, dactinomycin,daratumumab, darbepoetin a, dasatinib, daunorubicin hydrochloride,daunorubicin hydrochloride and cytarabine liposome, decitabine,defibrotide sodium, degarelix, denileukin diftitox, denosumab,dexamethasone, dexrazoxane hydrochloride, dinutuximab, docetaxel,doxorubicin hydrochloride, doxorubicin hydrochloride liposome,durvalumab, duvelisib, elotuzumab, eltrombopag olamine, emapalumab-lzsg,enasidenib mesylate, encorafenib, enzalutamide, epirubicinHydrochloride, EPOCH, epoetin alfa, erdafitinib, eribulin mesylate,erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus,exemestane, fec, filgrastim, fludarabine phosphate, fluorouracilinjection, fluorouracil-topical, flutamide, folfiri,folfiri-bevacizumab, folfiri-cetuximab, folfirinox, folfox, fostamatinibdisodium, FU-LV, fulvestrant, gefitinib, gemcitabine hydrochloride,gemcitabine-cisplatin, gemcitabine-oxaliplatin, gemtuzumab ozogamicin,gilteritinib fumarate, glasdegib maleate, glucarpidase, goserelinacetate, granisetron, HPV bivalent vaccine, HPV bivalent vaccine,recombinant HPV nonavalent vaccine, HPV nonavalent vaccine, recombinant,HPV quadrivalent vaccine, HPV uadrivalent vaccine recombinant,hydroxyurea, hyper-CVAD, ibritumomab tiuxetan, ibrutinib, ICE,idarubicin hydrochloride, idelalisib, ifosfamide, imatinib mesylate,imiquimod, inotuzumab ozogamicin, Interferon α-2b Recombinant,iobenguane I¹³¹, ipilimumab, irinotecan hydrochloride, irinotecanhydrochloride liposome, ivosidenib, ixabepilone, ixazomib citrate, JEB,lanreotide acetate, lapatinib ditosylate, larotrectinib sulfate,lenalidomide, lenvatinib mesylate, letrozole, leucovorin calcium,leuprolide acetate, lomustine, lorlatinib, lutetium Lu 177-dotatate,mechlorethamine hydrochloride, megestrol acetate, melphalan, melphalanhydrochloride, mercaptopurine, mesna, methotrexate, methylnaltrexonebromide, midostaurin, mitomycin c, mitoxantrone hydrochloride,mogamulizumab-kpkc, moxetumomab pasudotox-tdfk, MVAC, necitumumab,nelarabine, neratinib maleate, netupitant and palonosetronhydrochloride, nilotinib, nilutamide, niraparib tosylate monohydrate,nivolumab, obinutuzumab, OEPA, ofatumumab, OFF, olaparib, olaratumab,omacetaxine mepesuccinate, ondansetron hydrochloride, OPPA, osimertinibmesylate, oxaliplatin, paclitaxel, paclitaxel albumin-stabilizednanoparticle formulation, PAD, palbociclib, palifermin, palonosetronhydrochloride, palonosetron hydrochloride and netupitant, pamidronatedisodium, panitumumab, panobinostat, pazopanib hydrochloride, PCV, PEB,pegaspargase, pegfilgrastim, peginterferon α-2b, pembrolizumab,pemetrexed disodium, pertuzumab, plerixafor, polatuzumab vedotin-piiq,pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone,procarbazine hydrochloride, propranolol hydrochloride, radium 223dichloride, raloxifene hydrochloride, ramucirumab, rasburicase,ravulizumab-cwvz, R-CHOP, R-CVP, recombinant HPV bivalent vaccine,recombinant HPV nonavalent vaccine, recombinant HPV quadrivalentvaccine, recombinant interferon α-2b, regorafenib, R-EPOCH, ribociclib,R-ICE, rituximab, rituximab and hyaluronidase human, rolapitanthydrochloride, romidepsin, romiplostim, rucaparib camsylate, ruxolitinibphosphate, siltuximab, sipuleucel-t, sonidegib, sorafenib tosylate,STANFORD V, sunitinib malate, TAC, tagraxofusp-erzs, talazoparibtosylate, talc, talimogene laherparepvec, tamoxifen citrate,temozolomide, temsirolimus, thalidomide, thioguanine, thiotepa,tisagenlecleucel, tocilizumab, topotecan hydrochloride, toremifene, TPF,trabectedin, trametinib, trastuzumab, trastuzumab andhyaluronidase-oysk, trifluridine and tipiracil hydrochloride, uridinetriacetate, VAC, Valrubicin, VAMP, vandetanib, VeIP, vemurafenib,venetoclax, vinblastine sulfate, vincristine sulfate liposome,vinorelbine tartrate, vip, vismodegib, vorinostat, XELIRI, XELOX,Ziv-aflibercept, zoledronic acid, and combinations of any of theforegoing.

The efficacy of administering a selective IL-2Rβγc agonist or a compoundcomprising an IL-2Rβ ligand and/or an IL-2Rγc ligand provided by thepresent disclosure for treating cancer may be assessed using in vitroand animal studies and in clinical trials.

The suitability of a selective IL-2Rβγc agonist, a compound comprisingan IL-2Rβ ligand and/or an IL-2Rγc ligand provided by the presentdisclosure and/or pharmaceutical compositions of any of the foregoing intreating cancers listed above may be determined by methods described inthe art. For example, screens developed to demonstrate the anti-tumoractivity of oncolytic agents are known (Miller, et al., J Med Chem,1977, 20(3), 409-413; Sweeney, et al., Cancer Res, 1978, 38(9),2886-2891; and Weiss and Von Hoff, Semin Oncol, 1985, 12(3 Suppl 4),69-74). Accordingly, it is well with the capability of those of skill inthe art to assay and use the compounds and/or pharmaceuticalcompositions thereof to treat the above diseases or disorders.

Compounds provided by the present disclosure can be useful in treatingautoimmune diseases. Autoimmune diseases are defined as human diseasesin which the immune system attacks its own proteins, cells, and tissues.A comprehensive listing and review of autoimmune diseases can be foundin The Autoimmune Diseases (Rose and Mackay, 2014, Academic Press).

IL-2Rβγc agonists, compounds comprising an IL-2Rβ ligand and/or anIL-2Rγc ligand provided by the present disclosure and pharmaceuticalcompositions of any of the foregoing may be administered to a patient totreat an inflammatory disease or an autoimmune disease.

Examples of inflammatory diseases include allergy, Alzheimer's disease,anemia, ankylosing spondylitis, arthritis, atherosclerosis, asthma,autism, arthritis, carpal tunnel syndrome, celiac disease, colitis,Crohn's disease, congestive heart failure, dermatitis, diabetes,diverticulitis, eczema, fibromyalgia, fibrosis, gall bladder diseasegastroesophageal reflux disease, Hashimoto's thyroiditis, heart attack,hepatitis, irritable bowel syndrome, kidney failure, lupus, multiplesclerosis, nephritis, neuropathy, pancreatitis, Parkinson's disease,psoriasis, polymyalgia rheumatica, rheumatoid arthritis, scleroderma,stroke, surgical complications, and ulcerative colitis.

Examples of autoimmune diseases include Addison's disease,agammaglobulinemia, alopecia areata, amyloidosis, anklylosingspondylitis, anti-GBM/anti-TBN nephritis, antiphospholipid syndrome,autoimmune angioedema, autoimmune dysautonomia, autoimmuneencephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease,autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy,autoimmune urticaria, axonal and neuronal neuropathy, Balo disease,Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid,Castleman disease, celiac disease, Chagas disease, chronic inflammatorydemyelinating polyneuropathy, chronic recurrent multifocalosteomyelitis, Churg-Strauss, cicatricial pemphigoid, Cogan' syndrome,cold agglutinin disease, congenital heart block, Coxcackie myocarditits,CREST syndrome, Crohn's disease, dermatitis herpetiformis,dermatomyositis, Devic's disease, discoid lupus, Dressler's syndrome,endometriosis, eosinophilic esophagitis, eosinophilic fasciitis,erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome,fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cellmyocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosiswith polyangiitis, Graves' disease, Gullain-Barre syndrome, Hashimoto'thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpesgestationis or pemphigoid gestationis, hypogammaglobulinemia, IgAnephropahy, IgG4-related sclerosing disease, immune thrombocytopenicpurpura, inclusion body myositis, interstitial cystitis, juvenilearthritis, juvenile diabetes, juvenile myositis, Kawasaki disease,Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus,lichen sclerosus, ligneous conjunctivitis, linear IgA disease, lupus,Lyme disease chronic, Meniere's diseases, microscopic polyangiitis,mixed connective tissue disease, Mooren's ulcer, Mucha-Habermanndisease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy,neuromyelitis, optica, neutropenia, ocular cicatricial pemphigoid, opticneuritis, palindromic rheumatism, PANDAS, paraneoplastic cerebellardegeneration, paroxysmal nocturnal hemoglobinuria, Parry Rombergsyndrome, pars planitis, Parsonnage-Turner syndrome, pemphigus,peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia,POEMS syndrome, polyarteritis nodosa, polyglandular syndromes,polymyalgia rheumatica, polymyositis, postmyocardial infarctionsyndrome, postpericardiotomy syndrome, primary biliary cirrhosis,primary sclerosing cholangitis, progesterone dermatitis, psoriasis,psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum,Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy,relapsing polychondritis, restless legs syndrome, retroperitonealfibrosis, rheumatic fever, rheumatoid arthritis, sarcodosis, Schmidtsyndrome, scleritis, scleroderma, Sjogren's syndrome, sperm andtesticular autoimmunity, stiff person syndrome, subacute bacterialendocarditis, Susac's syndrome, sympathetic ophthalmia, Takayasu'sarteritis, temporal arteritis, thrombocytopenic purpura, Tolosa-Huntsyndrome, transverse myelitis, type 1 diabetes, ulcerative colitis,undifferentiated connective tissue disease, uveitis, vaculitis,vitiligo, and Wegener's granulomatosis.

A selective IL-2Rαβγc agonist, a compound comprising an IL-2Rβ ligandand/or an IL-2Rγc ligand, or a pharmaceutical composition comprising anyof the foregoing may be administered in conjunction with one or moreimmunosuppresants including, for example, corticosteroids such asprednisone, budesonide, and prednisolone; Janus kinase inhibitors suchas tofacitinib; calcineurin inhibitors such as cyclosporine andtacrolimus; mTOR inhibitors such as sirolimus and everolimus; IMDHinhibitors such as azathioprine, leflunomide, and mycophenolate;biologics such as abatacept adalimumab, anakinra, certolizumab,etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab,secukinumab, tocilizumab, ustekinumab, and vedolizumab; and monoclonalantibodies such as basiliximab and daclizumab.

IL-2Rβγc agonists, compounds comprising an IL-2R and/or an IL-2Rγcligand provided by the present disclosure and pharmaceuticalcompositions of any of the foregoing may be administered to a patient totreat a disease associated with the activation, proliferation,metabolism, and/or differentiation of T-cells.

IL-2Rβγc agonists, a compound comprising an IL-2Rβ and/or an IL-2Rγcligand provided by the present disclosure and pharmaceuticalcompositions of any of the foregoing may be administered to a patient totreat an organ transplant.

IL-2Rβγc agonists, compounds comprising an IL-2R and/or an IL-2Rγcligand provided by the present disclosure and pharmaceuticalcompositions of any of the foregoing may be administered to a patienttogether with another compound for treating an inflammatory disease oran autoimmune disease in the subject. The at least one other therapeuticagent may be a different IL-2Rβγc agonist or compound comprising anIL-2Rβ and/or an IL-2Rγc ligand provided by the present disclosure. AnIL-2Rβγc agonist or a compound comprising an IL-2R and/or an IL-2Rγcligand and the at least one other therapeutic agent may act additivelyor synergistically. The at least one additional therapeutic agent may beincluded in the same pharmaceutical composition or vehicle comprisingthe IL-2Rβγc agonist or a compound comprising an IL-2Rβ and/or anIL-2Rγc ligand or may be in a separate pharmaceutical composition orvehicle. Accordingly, methods provided by the present disclosure furtherinclude, in addition to administering an IL-2Rβγc agonist or a compoundcomprising an IL-2Rβ and/or an IL-2Rγc ligand, administering one or moretherapeutic agents effective for treating an inflammatory disease or anautoimmune disease or a different disease, disorder or condition than aninflammatory disease or an autoimmune disease. Methods provided by thepresent disclosure include administration of an IL-2Rβγc agonist or acompound comprising an IL-2R and/or an IL-2Rγc ligand and one or moreother therapeutic agents provided that the combined administration doesnot inhibit the therapeutic efficacy of an IL-2Rβγc agonist or acompound comprising an IL-2R and/or an IL-2Rγc ligand and/or does notproduce adverse combination effects.

Pharmaceutical compositions comprising an IL-2Rβγc agonist may or acompound comprising an IL-2Rβ and/or an IL-2Rγc ligand be administeredconcurrently with the administration of another therapeutic agent, whichmay be part of the same pharmaceutical composition as, or in a differentpharmaceutical composition than that comprising an IL-2Rβγc agonist or acompound comprising an IL-2R and/or an IL-2Rγc ligand. An IL-2Rβγcagonist or a compound comprising an IL-2Rβ and/or an IL-2Rγc ligand maybe administered prior or subsequent to administration of anothertherapeutic agent. In combination therapy, the combination therapy maycomprise alternating between administering an IL-2Rβγc agonist or acompound comprising an IL-2Rβ and/or an IL-2Rγc ligand and a compositioncomprising another therapeutic agent, e.g., to minimize adverse drugeffects associated with a particular drug. When an IL-2Rβγc agonist or acompound comprising an IL-2Rβ and/or an IL-2Rγc ligand is administeredconcurrently with another therapeutic agent that potentially may producean adverse drug effect including, for example, toxicity, the othertherapeutic agent may be administered at a dose that falls below thethreshold at which the adverse drug reaction is elicited.

Pharmaceutical compositions comprising an IL-2Rβγc agonist or a compoundcomprising an IL-2Rβ and/or an IL-2Rγc ligand may be administered withone or more substances to enhance, modulate and/or control release,bioavailability, therapeutic efficacy, therapeutic potency, stability,and the like of a compound of an IL-2Rβγc agonist or a compoundcomprising an IL-2Rβ and/or an IL-2Rγc and/or an IL-2Rβ and/or anIL-2Rγc ligand. For example, to enhance the therapeutic efficacy of anIL-2Rβγc agonist or a compound comprising an IL-2R and/or an IL-2Rγcligand, an IL-2Rβγc agonist or a compound comprising an IL-2Rβ and/or anIL-2Rγc ligand or a pharmaceutical composition of any of the foregoingmay be co-administered with one or more active agents to increase theabsorption or diffusion of the IL-2Rβγc agonist or the compoundcomprising an IL-2Rβ and/or an IL-2Rβ and/or an IL-2Rγc ligand from thegastrointestinal tract to the systemic circulation, or to inhibitdegradation of the IL-2Rβγc agonist or a compound comprising an IL-2Rβand/or an IL-2Rγc ligand in the blood of a subject. A pharmaceuticalcomposition comprising an IL-2Rβγc agonist or a compound comprising anIL-2Rβ and/or an IL-2Rγc ligand may be co-administered with an activeagent having pharmacological effects that enhance the therapeuticefficacy of the IL-2Rβγc agonist or a compound comprising an IL-2Rβand/or an IL-2Rγc ligand.

An IL-2Rβγc agonist, a compound comprising an IL-2Rβ and/or an IL-2Rγcligand, or a pharmaceutical composition comprising any of the foregoingmay be administered in conjunction with an agent known or believed to beeffective in treating an inflammatory disease or an autoimmune diseasein a patient.

An IL-2Rβγc agonist, a compound comprising an IL-2Rβ and/or an IL-2Rγcligand, or a pharmaceutical composition comprising any of the foregoingmay be administered in conjunction with an agent known or believed tointerfere with proliferation. An IL-2Rβγc agonist, a compound comprisingan IL-2Rβ and/or an IL-2Rγc ligand, or a pharmaceutical compositioncomprising any of the foregoing may be administered in conjunction withan agent known or believed to interfere with mitosis. An IL-2Rβγcagonist, a compound comprising an IL-2Rβ and/or an IL-2Rγc ligand, or apharmaceutical composition comprising any of the foregoing may beadministered in conjunction with an agent known or believed to interferewith DNA replication. An IL-2Rβγc agonist, a compound comprising anIL-2Rβ and/or an IL-2R and/or an IL-2Rγc ligand, or a pharmaceuticalcomposition comprising an IL-2Rβγc agonist may be administered inconjunction with an agent known or believed to interfere with DNArepair.

Compounds provided by the present disclosure can be useful in vitro astools for understanding the biological role of IL-2, including theevaluation of the many factors thought to influence, and be influencedby, the production of IL-2 and the receptor binding process. The presentcompounds are also useful in the development of other compounds thatbind to and activate the IL-2R, because the present compounds provideuseful information concerning the relationship between structure andactivity that should facilitate such development.

The compounds are also useful as competitive binders in assays to screenfor new IL-2 receptor antagonists. In such assay embodiments, thecompounds of the invention can be used without modification or can bemodified in a variety of ways; for example, by labeling, such ascovalently or non-covalently joining a moiety which directly orindirectly provides a detectable signal. In any of these assays, thematerials thereto can be labeled either directly or indirectly.Possibilities for direct labeling include label groups such as:radiolabels such as ¹²⁵I, enzymes such as peroxidase and alkalinephosphatase, and fluorescent labels capable of monitoring the change influorescence intensity, wavelength shift, or fluorescence polarization.Possibilities for indirect labeling include biotinylation of oneconstituent followed by binding to avidin coupled to one of the abovelabel groups. The compounds may also include spacers or linkers in caseswhere the compounds are to be attached to a solid support.

Based on their ability to bind to the IL-2 receptor, the peptidesprovided by the present disclosure can be used as reagents for detectingIL-2 receptors, for example, on living cells, fixed cells, in biologicalfluids, in tissue homogenates, in purified, and natural biologicalmaterials. For example, by labelling such peptides, one can identifycells having IL-2 receptor on their surfaces. In addition, based ontheir ability to bind the IL-2 receptor, the peptides of the presentinvention can be used, for example, in in situ staining, FACS(fluorescence-activated cell sorting), Western Blotting, and ELISA. Inaddition, based on their ability to bind to the IL-2 receptor, peptidesprovided by the present disclosure can be used in receptor purification,or in purifying cells expressing IL-2 receptors on the cell surface (orinside permeabilized cells).

The compounds provided by the present disclosure can also be utilized ascommercial reagents for various medical research and diagnostic uses.Such uses include, for example, (1) use as a calibration standard forquantitating the activities of candidate IL-2 agonists in a variety offunctional assays; (2) use to maintain the proliferation and growth ofIL-2-dependent cell lines; (3) use in structural analysis of the IL-2receptor through co-crystallization; (4) use to investigate themechanism of IL-2 signal transduction/receptor activation; and (5) otherresearch and diagnostic applications wherein the IL-2 receptor ispreferably activated or such activation is conveniently calibratedagainst a known quantity of an IL-2R agonist.

EXAMPLES

The following examples describe in detail methods used for determiningthe activity of peptides with the IL-2Rβ and IL-2Rγc subunits. It willbe apparent to those skilled in the art that many modifications, both tomaterials and methods, may be practiced without departing from the scopeof the disclosure. In the examples, the IL-2Rβ subunit refers to humanIL-2Rβ (CD122 protein, Fc Tag) (27-239), Accession No. NP_000869.1 andwas obtained from ACRObiosystems, Inc., product number ILB-H5253. TheIL-2Rγc subunit” refers to human IL-2Rγc (CD132 protein, Fc Tag)(23-254), Accession No. AAH14972 and was obtained from ACRObiosystems,Inc., product number ILG-H5256.

Example 1

Phage Display pIII Library Panning Against Fc-Receptor Fusions onMagnetic Beads (Acid Elution) Library Panning Procedure

Fifty (50) μL of Protein G Dynabeads® (Invitrogen) was used for eachlibrary sample. After resuspending the stock bottle, the desired volumeof beads was transferred to a sterile microfuge tube and applied to themagnet.

With the beads on a magnet, the supernatant was removed, and the beadswere washed with 1 mL of PT buffer (1×PBS, 0.05% Tween®20).

The supernatant was removed and 1 mL of PBS+1% BSA+0.05% Tween®20 wasadded and mixed at 25° C. for at least 1 hour to block the beads.

A tube was applied to the magnet and the blocking solution was removed.For each library to be tested, 5 pg of a Fc-fused receptor of interestwas added to each library sample for each round to bring the totalvolume to at least 400 μL. The samples were mixed at 25° C. for at least1 h. The sample was applied to the magnet and the supernatant wasremoved.

Two-hundred 200 μL of PT buffer was added for each 50 μL of bead. Thesample was thoroughly mixed and 200 μL aliquots were transferred intotubes that were pre-labeled for each library to be screened. Anadditional 500 μL of PT was added to each tube, the samples mixed, andthen applied to the magnet. A total of 700 μL/tube was used for thewash.

One (1) mL aliquots of the libraries removed from the −20° C. freezer.One-hundred (1000 μL of 10× BT buffer (5% BSA, 0.5% Tween®20 in 1×PBS)was added to each tube and vortexed. The library samples weretransferred to pre-labeled tubes containing beads. The samples were thenincubated at 4° C. on the rotator for at least 2 h. For the additionalrounds of screening, 1 mL aliquots of the amplification from theprevious round from each library was used. The beads were recovered withthe magnet and the phage solution removed. The beads were washed 2× with1 mL of PT buffer. Five-hundred (500) μL of PT buffer was added and thesuspension was transferred to a clean tube. The beads were recovered onthe magnet and the final wash removed.

Four-hundred seventy-five (475) μL of phage elution buffer was added toeach well (0.2 M glycine-HCL, pH 2.2, 1 mg/mL BSA). The samples wereincubated at 25° C. for 10 min on the rotator. The beads were recoveredon the magnet and the eluted phage transferred to a clean tube.

Twenty-five (25) μL of neutralization buffer (2 M Tris Base) was addedto the 475 μL of elution. The neutralized samples were maintained at 4°C. until the TG1 cells were ready amplification. The samples were storedat −20° C. after screening. Fifty (50) μL (about 10% of the totalvolume) was transferred to a 1.5 mL microfuge tube and store at −20° C.for use in deep sequencing.

Example 2 TG1 Culture and Library Amplification

A fresh TG1 (or OmniMax) culture was grown for about 1 to 1.5 h afteradding the libraries to the beads. 2X-YT medium (10 mL) was placed intoa 50 mL Falcon® tube. Two-hundred (200) μL of the TG1 overnight wasadded to the falcon tube. 2X-YT medium (600 μL) was placed in a cuvettefor OD600 blank. The culture was grown at 250 rpm and 37° C., taking thefirst OD measurement after 60 min. The TG1 cells should be in log phaseat the time of use with an OD600 of 0.5-0.7.

Eluted phage (400 μL to 450 μL) was added to 1 mL of the TG1 cells at anOD600 of 0.5-0.7 in a 50 mL Falcon® tube. The phage and TG1 cells wereincubated at 37° C. for 30 min without shaking. About 50 to 100 μL wasset aside for titering and characterization.

2YT medium (10.5 mL) was added to 12 μL of carbenicillin (carb) (100mg/mL to make 100 μg/mL) and 24 μL of 50% glucose (to make 0.1% glucose)and the cells incubated while shaking at 37° C. at 250 rpm for 1 h.

M13K07 helper phage (5×10¹⁰ pfu, 24 μL of the stock, 2×10¹² pfu/mL) wasthen added and swirled to mix. The phage and cells were incubated at 37°C. for 30 min without shaking.

Kanamycin was diluted to 3 mg/mL and arabinose to 2.4% in 2YTmedium/Carbenicillin-100/0.1% glucose and 100 μL was added to eachamplification. The mixture was incubated overnight at 37° C. and 250rpm.

The culture was transferred to a 50 mL high-speed VWR centrifuge tubeand centrifuged at 8,000 g for 15 min at 4° C. in a JSP-F50C centrifugeto pellet the cells.

The supernatant was transferred to a 50 mL high-speed VWR centrifugetube and 0.2 volumes of PEG/NaCl (multiply the volume by 0.25 mL to 3 mLPEG/NaCl for 12 mL amplification) was added, mixed, and incubated on icefor 30 minutes.

The cells were then centrifuge at 10,500 g for 15 min at 4° C. in aJSP-F50C centrifuge. The supernatant was removed, and the phage pelletwas resuspended in a total of 1 mL of PBT (1×PBS, 0.05% Tween®20, 0.5%BSA) by pipetting.

The sample was transferred to an Eppendorf tube, vortexed, andcentrifuged at 12,000 rpm for 30 sec. The supernatant was transferred toa clean Eppendorf tube and stored at 4° C. This amplified phage sample(250-500 μL) was used for the next round of screening.

Example 3 Preparation of Cultures from Individual Colonies

Ninety-six (96) wells of a deep well plate were filled with 1 mL of 2YTbroth/Ampicillin-50/0.1% glucose. Ninety-six (96) colonies were placedinto the wells using P20 tips. The tips were left in the wells to markthe position. The tips were removed using a multi-channel pipette afterthe entire plate was completed. The plate was covered with a breathablefilm.

The inoculated plate(s) were incubated in a shaker at 37° C. until thecultures became turbid, typically within 4 h at 250 rpm.

The plate(s) was removed from the incubator and 50 μL of the culturefrom each well was removed to another deep well block designated as the“Archive Block” containing 1 mL of 2YT broth/Ampicillin-50/0.1% glucose.The plate(s) were covered with a breathable film and incubated overnightat 37° C. and 250 rpm.

After incubating overnight, M13K07 helper phage was added to 2×10¹⁰pfu/mL in 2YT broth/Ampicillin-50/0.1% glucose (make 6.0 mL per block).Fifty (50) μL of the diluted M13K07 was added to each culture well inthe deep well block. The deep well block was covered with breathablefilm and incubated for 30 min at 37° C. and 250 rpm.

Kanamycin was diluted to 0.5 mg/ml and arabinose to 0.4% in 2YTbroth/Ampicillin-50/0.1% glucose (make 6.0 ml per block) and 50 μL wasadded to each well. The plate was covered with a breathable film andincubated overnight at 37° C. and 250 rpm.

The “Archive Block” culture was removed from the incubator and 50 μL wastransferred to a 96-well plate containing 50 μL of 50% glycerol. Theplate was sealed with foil and stored at −80° C. The remaining culturein the block was covered with a foil seal and stored at 4° C.

The block was centrifuged and inoculated with M13K07 at 4000 rpm for 15min. While avoiding the bacterial pellet, 850 μL of the phagesupernatant was transferred to a fresh deep well plate, covered with afoil seal, and stored at 4° C.

Example 4 ELISA Protocol for Fc-Receptor Fusions

For each block to be assayed, a 1×96 well ELISA plate was coated withFc-receptor fusion (1 μg/mL in PBS) at 50 μL/well. The wells wereincubated at 25° C. for at least 1 h.

The Fc-receptor fusion was removed from each well. Three-hundred (300)μL of blocking buffer (1×PBS, 1% BSA) was added to each well of areceptor-coated plate. Plates were covered with film and left at 37° C.for 1 h or overnight at 4° C.

The plate was washed 4 times with PT (1×PBS, 0.05% Tween®20) buffer.

Fifty (50) μL of PBT was added to each well. Fifty (50) μL of the phagesupernatant from the block was added to each well and incubated at 4° C.for 1 h.

The plates were washed 4 times with cold PT.

To each well 100 μL of anti-M13-HRP antibody diluted 1:5000 in cold PBTwas added. The wells were incubated for 1 h at 4° C.

The plates were then washed 4 times with cold PT.

Fifty (50) μL of TMB was then added to each well, and the wells wereincubated for 1-10 min at 25° C. Fifty (50) μL of a “stop” solution wasadded and the plate read at 450 nm.

Example 5 Evaluation of Peptide Heterodimer Ability to Dimerize IL-2Rβγcand to Activate IL-2 Responsive Cells

Following the identification of ligands that exhibit IL-2R and IL-2Rγcbinding activity, compounds were identified that exhibit IL-2R agonistactivity. This involved assessing the ability of the peptide to dimerizethe IL-2Rβγc subunits and to signal in cell-based assays. Dimerizationis a necessary, but not sufficient, step in the activation of receptorsignaling. To assess agonist activity in cell-based assays, IL-2responsive cell lines were tested for an indicator of IL-2 signaling,phosphorylation of STAT5. Compounds that exhibited IL-2Rβγc agonistactivity in these cell lines were then be tested in primary humanperipheral blood mononuclear cells (PBMC) for IL-2R agonism, and for thedesired selectivity favoring activation of cell types expressingIL-2Rβγc subunits, but with low or no IL-2Rα (CD25) subunit expression.

Dimerization potential was assessed using a β-Gal complementation systemin which a portion of the intracellular domains of each respective IL-2receptor subunit was replaced with functionally complementary fragmentsof β-Gal, which regain catalytic activity when brought into sufficientlyproximity. Cells expressing these constructs generate β-Gal activity,with an IC₅₀ of about 26 nM, when treated with IL-2 (see DiscoverXproduct specifications). All synthetic, potentially agonist, peptideswere tested using this assay.

Candidate compounds were scored for induction of STAT5 phosphorylationin two cell lines: (1) NK-92 cells, a human cell line that expresses allthree IL-2 receptor subunits, and which were responsive toIL-2Rβγc-biased variants as well as wild type IL-2; and (2) TF-1β cells,derived from the human erythroleukemia line TF-1, which naturallyexpresses only IL-2Rγc, and was engineered to be IL-2 responsive bytransfection of IL-2Rβ. TF-1β was constructed and IL-2R subunitexpression levels in both cell lines were verified by QPCR and FACSanalysis.

Compounds were tested in both cell lines. Dose response assays wereconducted to determine the IC₅₀ of the test compounds and to compare thetest compounds with IL-2 as an indicator of IL-2Rβγc receptor bias.

The conferring of IL-2 responsiveness on TF-1 cells by transfection andexpression of the IL-2Rβ subunit demonstrates that peptide agonistactivity is dependent on the presence of the IL-2Rβ subunit. Todetermine that compound activity was not due to contamination withcytokines, or to an indirect action of the peptide inducing productionof IL-2 or IL-15, neutralizing antibodies (R&D Systems) against IL-2 andIL-15 were included in the activity assay and shown to inhibit theactivity of IL-2 and IL-15 but had no effect on the agonist activity ofthe test peptides.

Compounds exhibiting IL-2R agonist activity in the cell lines weretested on human primary immune cells, PBMCs, collected from individualdonors (commercially available from Lonza), and in some cases onpurified CD4+ cells (Lonza). A substantial fraction of PBMCs from normaldonors were responsive to IL-2. To assess IL-2 agonist activity of thetest compounds, cells were exposed to the compounds or IL-2 and scoredfor STAT5 phosphorylation by Western Blot analysis. Those compoundsexhibiting STAT5 activation of PBMCs were subjected to a follow-on assaydesigned to assess subunit bias of the compounds compared to IL-2. Thisassay involved determining a dose response of the test compounds andIL-2 (1 to 1000 IU) over 30 min, scored by a FACS-based protocolallowing detection of both intracellular pSTAT5 as an indicator of IL-2Ractivation, and cell surface CD25, the IL-2Rα subunit. Cells expressingthe three IL-2R subunits, IL-2Rαβγc, bind IL-2 with very high affinity(about 10 pM) and are therefore sensitive to low concentrations of IL-2;whereas cells expressing only IL-2Rβγc (about 1 nM affinity) requireexposure to substantially higher IL-2 levels for activation. Becausecompounds provided by the present disclosure were selected for bindingto the IL-2Rβ and IL-2Rγc subunits, but not to the IL-2Rα subunit, thepotency of the compounds is expected to be uncorrelated with the levelof expression of IL-2Rα on cells; and comparison of response profiles ofcells treated with compounds provided by the present disclosure ortreated with IL-2 should reveal any bias.

Example 6 Identified Peptides

Four stochastic libraries with each library containing approximately10¹⁰ independent recombinants, with each clone potentially displaying aunique peptide sequence have been screened for binding to individualhuman IL-2Rβ and IL-2Rγc subunits. In screening these four initiallibraries against the Rβ subunit extracellular domain (ECD), 98 uniquepeptide clones were identified and confirmed as ligands of IL-2Rβ. TheseIL-2Rβ ligands can be grouped into at least two sequence families:family 1 and family 2.

In screening the four initial libraries against the γc subunit, 15unique peptide sequences have been identified, which on first analysisof this limited number of clones, suggests that these may represent morethan one distinct sequence family. At the current level of resolutionthese peptide sequences appear to have no sequence similarity to humanIL-2. Most of the peptides so far recovered have been tested for bindingto the IL-2Rβ and/or IL-2Rγc subunits, and all peptides tested werefound to bind only to the subunit against which they were selected (byphage ELISA; capable of detecting affinities as weak as 10-50 μM).

An analysis of a sample of the identified peptides was performed todetermine human and mouse receptor specificity. Initially selected onhuman IL-2 receptors, none of the IL-2Rβ ligands and IL-2Rγc ligandsbound only to the corresponding human subunit.

Peptides having SEQ ID NO: 377 to SEQ ID NO: 399 have been synthesizedand have been evaluated for IL-2Rβ and IL-2Rγc activity. Peptides havingSEQ ID NO: 377 to SEQ ID NO: 385 include an IL-2Rβ ligand and peptideshaving SEQ ID NO: 386 to SEQ ID NO: 399 include an IL-2Rγc ligand.

SEQ ID NO: 377 G G F R C W E A P V G E I C E L G G NH₂ SEQ ID NO: 378G G I E C E R A Q I G E V C Q I G G NH₂ SEQ ID NO: 379G G M E C F L A A V G Q I C E L G G NH₂ SEQ ID NO: 380G G Y D C R I A Q V G E L C D L G G NH₂ SEQ ID NO: 381G G E I C N V G Q V W P D C L L G G NH₂ SEQ ID NO: 382G G N M C L V G D Y W P S C Q I G G NH₂ SEQ ID NO: 383G G Q I C D V G Q W W P D C Q V G G NH₂ SEQ ID NO: 384C Y E V G D Y C Q S F L G G NH₂ SEQ ID NO: 385R W G D V G D L L M P L G G NH₂ SEQ ID NO: 386D L S D L C T F W L S Q G G NH₂ SEQ ID NO: 387D L S D L S T F W L S Q G G NH₂ SEQ ID NO: 388D C S M W E G V E L C W G G NH₂ SEQ ID NO: 389G G L C F S E F L G E W V D C N G G NH₂ SEQ ID NO: 390G G V C S F D E A W G E W I C E G G NH₂ SEQ ID NO: 391G G K V C E M W G G V L L C W N G G R NH₂ SEQ ID NO: 392G G R T C T E W E N V V L C W V G G NH₂ SEQ ID NO: 393G G I L C Q D W S G 1 E I C W S G G R NH₂ SEQ ID NO: 394G G L I C Y T Y E G V E L C W Q G G R NH₂ SEQ ID NO: 395G G V M C E R W Q G V E L C W L G G NH₂ SEQ ID NO: 396G G M C W L E W G E W V G S C L G G R NH₂ SEQ ID NO: 397G G C Y V V Y N Y Q E F R Y L C G G R NH₂ SEQ ID NO: 398G G L Y C R D N D G T Q Y C E T G G NH₂ SEQ ID NO: 399G G V V C Q D W E G V E L C W Q G G R NH₂

Example 7 Preparation of NK-92 Cells for Testing STAT5 Activation

NK-92 cells were seeded in a 24-well plate at 4×10⁵ cells, in 1 mLstarvation medium (SM), and incubated overnight at 37° C., 5% CO₂. Thestarvation medium contained RPMI 1640+20% FBS+2 mM L-glutamine+1 mMNaPyr+10 mM HEPES+0.1 mM BME (no rhIL-2 supplement).

Treatment mixtures were of 1 pg/mL Anti-hIL-2 neutralizing antibody (0.2mg/mL stock) or goat IgG control (1 mg/mL stock) were prepared.

The treatment mixtures and the antibody mix were added to the cells for30 min at 37° C., 5% CO₂. Each sample was then transferred to a 1.5 mLmicrofuge tube and spun down at 1,500 RPM for 5 minutes. The cells werewashed in 1 mL PBS and centrifuged again.

A phosphatase and protease inhibitor cocktail (Thermo #78442) were addedto mPER buffer at a 1:100 dilution. After the cells were pelleted, 50 μLof mPER buffer was added to each sample and pipetted repeatedly tohomogenize.

The lysates were centrifuged at 14,000 RPM for 5 min at RT. Thesupernatants were transferred to clean tubes and stored frozen at −80°C.

The human IL-2 Antibody (goat IgG) was obtained from R&D Systems No.AF-202-NA; the normal goat IgG Control was obtained from R&D Systems No.AB-108-C; the Anti-STAT5 Antibody (rabbit), the Cell Signaling No.94205S, the Anti-pSTAT5 Antibody (rabbit), the Cell Signaling No. 4322S,and the Goat anti-rabbit IgG-HRP was obtained from JacksonImmunoresearch No. 111-035-144.

The antibodies, treatment and working stock prep for each of the samplesis provided in Table 1. Compounds A and B are IL-2Rβγc agonists providedby the present disclosure.

TABLE 1 STAT5 activation samples in NK-92 cells. Vol Vol No. Antibody(μL) Treatment (μL) Working stock prep 1 Anti-hIL-2 IgG 5 A 10 μM 100100 μM (1:100 of 10 mM stock in SM) 2 Anti-hIL-2 IgG 5 A 1 μM 10 100 μM(1:100 of 10 mM stock in SM) 3 Anti-hIL-2 IgG 5 A 0.1 μM 1 100 μM (1:100of 10 mM stock in SM) 4 Anti-hIL-2 IgG 5 B 10 μM 100 100 μM (1:100 of 10mM stock in SM) 5 Anti-hIL-2 IgG 5 B 1 μM 10 100 μM (1:100 of 10 mMstock in SM) 6 Anti-hIL-2 IgG 5 B 0.1 μM 1 100 μM (1:100 of 10 mM stockin SM) 7 Anti-hIL-2 IgG 5 rh-IL2 1 ng/mL 10 100 ng/mL (1:1000 of 100μg/mL stock in SM) 8 Anti-hIL-2 IgG 5 rhIL-2 0.1 ng/mL 1 100 ng/mL(1:1000 of 100 μg/mL stock in SM) 9 Anti-hIL-2 IgG 5 rhIL-2 0.1 ng/mL +1 100 ng/mL (1:1000 of 1% DMSO 100 μg/mL stock in SM) + 10 μL DMSO 10Anti-hIL-2 IgG 5 Starvation Medium N/A N/A (SM) 11 Goat IgG control 1 A10 μM 100 100 μM (1:100 of 10 mM stock in SM) 12 Goat IgG control 1 A 1μM 10 100 μM (1:100 of 10 mM stock in SM) 13 Goat IgG control 1 A 0.1 μM1 100 μM (1:100 of 10 mM stock in SM) 14 Goat IgG control 1 B 10 μM 100100 μM (1:100 of 10 mM stock in SM) 15 Goat IgG control 1 B 1 μM 10 100μM (1:100 of 10 mM stock in SM) 16 Goat IgG control 1 B 0.1 μM 1 100 μM(1:100 of 10 mM stock in SM) 17 Goat IgG control 1 rh-IL2 1 ng/mL 10 100ng/mL (1:1000 of 100 μg/mL stock in SM) 18 Goat IgG control 1 rhIL-2 0.1ng/mL 1 100 ng/mL (1:1000 of 100 μg/mL stock in SM) 19 Goat IgG control1 rhIL-2 0.1 ng/mL + 1 100 ng/mL (1:1000 of 1% DMSO 100 μg/mL stock inSM) + 10 μL DMSO 20 Goat IgG control 1 Starvation Medium N/A N/A (SM)

The samples were applied to a Western Blot and the result are shown inFIG. 1 . In the Western Blot shown in FIG. 1 , sample numbers 1-10 wereprobed with an anti-pSTAT5 antibody, sample numbers 1-10 were probedwith an anti-STAT5 antibody, sample numbers 11-20 were probed with ananti-pSTAT5 antibody, and sample numbers 11-20 were probed withanti-STAT5 antibody. The treatment reagents included Anti-STAT5 Antibody(rabbit), Cell Signaling No. 94205S; Anti-pSTAT5 Antibody (rabbit), CellSignaling No. 4322S; and Goat anti-rabbit IgG-HRP, JacksonImmunoresearch No. 111-035-144.

Compounds A and B induced (in a dose-responsive manner) STAT5phosphorylation (pSTAT5). As shown in FIG. 1 , the first 2 sets of threelanes include the two test compounds, and the next three lanes are theIL-2 positive controls. The final lanes (10) are ‘starved” cells showingno background of pSTAT5 in the starting cell population. Compound Arefers to a heterodimer of SEQ. ID. NO: 58 and SEQ ID. NO. 224. CompoundB refers to a heterodimer of SEQ. ID. NO: 58 and SEQ ID. NO. 237.

In the top row of lanes, are the results of a control experiment whichwas designed to rule out the possibility that the test samples werecontaminated with IL-2. To evaluate for contamination, the samemanipulations as in the lanes described above were performed, exceptthat an IL-2 neutralizing antibody was added to all samples. As is shownin lanes 7-9, the IL-2 controls were suppressed by this treatment, butthe test compound lanes (1-6) show about the same results as the minusAb lanes, demonstrating that the activity in the compound lanes is notdue to contaminating IL-2. In addition, the lane 9 control has a highamount of added DMSO (1%), the diluent for the peptide compound.Addition of DMSO causes no STAT5 phosphorylation.

The activation of STAT5, ERK1/2 and AKT in NK-92 cells by IL-2Rβγcagonists A and B provided by the present disclosure is shown in FIG. 3 .IL-2Rβγc agonist A refers to a heterodimer of SEQ. ID. NO: 58 and SEQID. NO. 224. IL-2Rβγc agonist B refers to a heterodimer of SEQ. ID. NO:58 and SEQ ID. NO. 237.

pSTAT5 dose response curves for L-2Rβγc agonists A and B in NK-92 cellsare shown in FIGS. 4A and 4B.

The results of a NK-92 cell proliferation assay using IL-2Rβγc agonistsA and B, rhIL-2 and other peptides C-G is shown in FIGS. 5A-5C.Compounds A-G are defined as in Table 2:

TABLE 2 Composition of peptides A-G. Peptide Composition A Heterodimerof E and F B Heterodimer of E and G C IL-27R/gpl30 heterodimer D gpl30homodimer E IL-2Rβ ligand; SEQ ID. NO. 58 F IL-2Rγc ligand; SEQ ID. NO.224 G IL-2Rγc ligand; SEQ ID. NO. 237

To perform the assay, NK-92 cells were plated in starvation medium at20,000 cells/well in a 96-well plate. Treatment was added to each wellin 3-fold serial dilutions with the peptides having maximumconcentration of 10 μM and rhL-2 having a maximum concentration of 6.67nM. The cells were then incubated at 37° C. for 48 h. CellTiter-Glo®reagent was added and the cells incubated for 10 min at 25° C. beforeluminescence reading. FIG. 5A shows the RLU for the peptide samples,FIG. 5B for the rhIL-2 sample, and FIG. 5C shows an overlay of FIGS. 5Aand 5B.

Example 8 Preparation of TF-16 and TF-1 Cells for Testing STAT5Activation

TF-1β and TF-1 parental cells were counted. The cells were collected and2.5×10⁶ cells pelleted at 200×g for 5 minutes. The pelleted cells werewashed with 25 mL RPMI with no additives.

The TF-1β and TF-1 parental cells were seeded at 5×10⁵ cells in a T25flask, in 5 mL starvation medium (SM), and incubated overnight with theflask upright at 37° C. under 5% CO₂.

The TF-1β and TF-1 parental cells were counted, and the viability wasdetermined. If necessary, the cells were diluted to 5×10⁵ cells/mL in SMand then 1 mL of the suspension was added to 6 wells/cell line of a24-well dish and incubate at 37° C. under 5% CO₂.

The treatments (see Example 7) were added to the cells for 30 min at 37°C. under 5% CO₂. The treated cells were transferred to a 1.5 mLmicrofuge tube and spun down at 1,500 RPM for 5 min. The cells werewashed in 1 mL PBS, centrifuged again, and the supernatant aspirated.The treatment reagents included Anti-STAT5 Antibody (rabbit), CellSignaling No. 94205S; Anti-pSTAT5 Antibody (rabbit), Cell Signaling No.4322S; and Goat anti-rabbit IgG-HRP, Jackson Immunoresearch No.111-035-144.

A phosphatase and protease inhibitor cocktail (Thermo No. 78442) wereadded to mPER buffer at 1:100 dilution. After the cells were pelleted,add 50 μL of mPER buffer was added to each sample and the mixturerepeatedly pipetted to homogenize.

The lysates were centrifuged at 14,000 RPM for 5 min at 25° C. Thesupernatants were transferred to clean tubes and stored frozen at −80°C.

The antibodies, treatment and working stock prep for each of the samplesis provided in Table 3. Compounds A and B are IL-2Rβγc agonists providedby the present disclosure.

TABLE 3 STAT5 activation samples in TF-1β and TF-1 cells. Vol # Cellline Treatment (μL) Working stock prep 1 TF-1β A 10 μM 100 100 μM (1:100of 10 mM stock in SM) 2 TF-1β B 10 μM 100 100 μM (1:100 of 10 mM stockin SM) 3 TF-1β C 10 μM 100 100 μM (1:100 of 10 mM stock in SM) 4 TF-1βrhIL-2 1 ng/mL 10 100 ng/mL (1:1000 of 100 μg/mL stock in SM) 5 TF-1βStarvation Medium¹ 100 N/A (SM) 6 TF-1β A 10 μM 100 100 μM (1:100 of 10mM stock in SM) 7 TF-1β B 10 μM 100 100 μM (1:100 of 10 mM stock in SM)8 TF-1β C 10 μM 100 100 μM (1:100 of 10 mM stock in SM) 9 rhIL-2 1 ng/mL10 100 ng/mL (1:1000 of 100 μg/mL stock in SM) 10 TF-1β StarvationMedium¹ 100 N/A (SM) ¹ Starvation medium: RPMI 1640, 2.5 g/L glucose(4.5 g/L total), 5% FBS, 2 mM L-glutamine, 1 mM NaPyr, and 10 mM HEPES(no GM-CSF supplement).

The samples were applied to a Western Blot and the results are shown inFIG. 2A.

RT-qPCR gene expression profiling comparing several TF-1β cells cellpopulations (G418 concentration varied) transfected with full lengthIL-2R used in the peptide simulation pSTAT5 evaluation is shown in Table4, and in FIG. 2B. In FIG. 2B, the relative expression level wasnormalized to GAPDH=1×10⁶ copies (REL=1×10⁶×2^((Ctgraph-Cttarget))).

TABLE 4 RT-qPCR gene expression profiles of TF-1 and TF-1β cellstransfected with IL-2Rβ. TF-1 TF-1 TF-1β TF-1β TF-1β TF-1β Target (ATCC)Control 2A 2B 3A 3B IL-2Rα 224 209 202 200 170 139 IL-2Rβ 1,329 1,17744,029 39,122 36,941 28,685 IL-2Rγ 35,258 18,886 28,492 23,508 27,25324,511

Example 9 pH Selective Screening

The IL-2Rβ subunit was screened with two peptide libraries to identifypeptides exhibiting pH-dependent affinity for the receptor subunit. Thescreening approach utilized cycles of binding and elution under variousacidic and neutral pH conditions.

Example 10 Phage Screening ELISA Protocol for pH-Dependence

The binding of phage to IL-2Rβ-GPI was determined using phage ELISA atthe two target pH values and the percent change in binding at pH 7.4relative to binding at pH 6.0 was calculated. Results for severalpeptides are shown in FIG. 6 . Well G03 is an example of a phagedisplaying pH-dependent binding to IL-2Rβ.

FIG. 7 shows an example of phage clones exhibiting pH-dependent binding(17E01, 17G03, 18A08, 17H07) compared to a non-pH dependent clone thatexhibited similar binding affinity at both pH 6.0 and pH 7.4 (negativeclone).

Example 11 ELISA Protocol for pH-Dependent Phage Titration

The ELISA screening protocol described in Example 10 was used with thefollowing differences: (1) all 96-well ELISA plates contained IL-2Rf-GPItarget; and (2) the titration of the phage supernatants was prepared in2 different PBT pH buffers; pH 6.0 and pH 7.4.

Phage titration was performed in a 96-well polypropylene plate using thefollowing procedure. A 3-times dilution of phage in PBT pH 6 buffer andpH 7.4 buffer was prepared. One-hundred (100) μL of the diluted phagewere transferred to the target-coated assay plate and incubated at 4° C.for 1 h.

The pH 6.0 wells were washed 3 times with cold PT pH 6.0 and the pH 7.4wells were washed 2 times with cold PT pH 7.4.

The bound phage were detected with anti-M13-HRP.

Binding curves for a pH-independent peptide that exhibited similarbinding at pH 6.0 and pH 7.4 are shown in FIG. 8A and binding curves fora pH-dependent clone are show FIG. 8B.

Example 12

ELISA Protocol for Biotinylated Peptide pH-Dependent Binding(IL-2Rβ/Fc-Receptor Binding/Multivalent)

For each peptide to be assayed, 16 ELISA plate wells were coated withneutravidin (10 pg/mL in PBS pH7.2) at 50 μL/well. The coated wells wereincubated at 25° C. for at least 1 h.

The neutravidin was removed from each well. Three-hundred (300) μL ofblocking buffer (1×PBS pH 7.2, 1% BSA) was added to each well of theneutravidin-coated plates. All plates were covered and maintained at 25°C. for 1 h or overnight at 4° C.

The incubated plates were washed 4 times with PT (1×PBS pH 7.2, 0.05%Tween®20) buffer.

The biotinylated peptides were diluted to 1 μM in PBT pH 7.2 buffer and50 uL was added to the appropriate 16 wells (8 for each binding pH). Theplates were incubated at 25° C. for at least 1 h.

Two (2) titrations of IL-2Rβ-Fc protein were prepared in a polypropyleneplate starting at 2 μg/mL using PBT pH 6.0 and pH 7.4 and diluting3-fold.

The plates were washed 4-times with PT (1×PBS pH 7.2, 0.05% Tween®20)buffer.

Fifty (50) μL of the IL-2Rβ-Fc protein dilutions were added to the assayplates buffered at pH 6.0 or pH 7.4) and incubated for 1 h at 4° C.

The incubated plates were washed 3-times with the corresponding pHbuffer PT (50 mM PBS pH 6.0, 0.05% Tween®20 or 50 mM PBS pH 7.4, 0.05%Tween®20).

Fifty (50) μL of goat anti-huIgG-HRP diluted 1:2500 in cold PBT pH 6.0was added to each well. The plates were then Incubated for 1 h at 4° C.

The plates were then washed 4 times with cold PT pH 6.0. Fifty (50) μLof TMB was then added to each well, and the wells were incubated for1-10 min at 25° C. Fifty (50) μL of a “stop” solution was added to eachwell, and the plates were read at 450 nm.

IL-2Rβ-Fc binding curves comparing a peptide exhibiting pH-independentbinding at pH 6.0 and pH 7.4 and a pH-dependent peptide is shown inFIGS. 9A and 9B, respectively. Fc binding is a multivalent interactionand therefore an over estimate of monovalent binding.

Example 13 Specific Heterodimeric IL-2Rβγc Agonist

A heterodimer was constructed by linking the C-terminus of IL-2Rγcligand having SEQ ID NO: 58 to the C-terminus of IL-2Rβ ligand havingSEQ ID NO. 224 with a linker comprising 4 amino acids and having alength of about 34 Å using standard click chemistry methods.

The heterodimer was incubated with NK92 cells and the STAT5phosphorylation measured as a function of concentration using themethods described in Examples 7 and 8. The results are presented in FIG.10 .

Example 14 Specific Heterodimer

A heterodimer was constructed by linking an IL-2Rβ ligand provided bythe present disclosure to an IL-2Rγc ligand provided by the presentdisclosure with a linker comprising from 3 to 6 amino acids usingstandard click chemistry methods.

Example 15 pSTAT5 Activation in NK92 and TF1-β Cells

The expression levels of the IL-2R subunits in NK92 and TF-1β cells wasdetermined using RT-qPCR gene expression profiling. The results arepresented in Table 5.

The heterodimer of Example 14 was incubated with NK92 cells and TF-1βcells and the STAT5 phosphorylation measured as a function ofconcentration using the methods described in Examples 7 and 8. Theresults are presented in Table 5.

TABLE 5 IL-Rαβγc subunit expression levels and STAT5 phosphorylation.NK92 Cells TF-1β Cells IL-2Rα¹ 111,181 194 IL-2Rβ¹ 303,457 227,488IL-2Rγc¹ 609,073 43,169 EC₅₀ (M) <10⁻⁸ <10⁻⁸ ¹Relative expression level:normalized to GAPDH = 1 × 10⁶ copies; REL = 1E⁶ × 2^((Ctgapdh−Cttarget))

Example 15 Proliferation of NK-92 Cells

The proliferation of NK-92 cells was determined using the proceduredescribed in Example 7.

The EC₅₀ for NK-92 cell proliferation for the heterodimer of Example 14was <10⁻⁸ M.

Example 16 pSTAT5 Activation in Human T-Cells

pSTAT5 activation of resting CD8 T-cells, resting CD4 T-cells, andresting Treg (CD25hi CD127lo) cells by the heterodimer of Example 14 wasdetermined using the method described in Example 17.

The incubation time was 30 min and pSTAT5 was measured by flowcytometry.

The heterodimer of Example 14 exhibited a similar potency in thedifferent human T-cell populations tested. In comparison, IL-2 has apotency bias for Treg and CD4 T-cells.

Example 17 STAT5 Phosphorylation in Resting and Activated Human CD-8T-Cells

CD8 T-cells were isolated using the entire PBMC pool with an EasySep™Human CD8+ T Cell Isolation Kit commercially available from STEMCELL™Technologies Inc.

Treg cells were isolated using the entire PBMC pool with an EasySep™Human CD4+CD127 lowCD25+ Regulatory T-Cell Isolation Kit commerciallyavailable from STEMCELL™ Technologies Inc.

For the resting group, the pSTAT5 assay was preformed and the lysatesfrozen at −180° C. until ELISA measurement.

For the activation group, cells were resuspended at 10⁶ cells/mL in CTSOpTmizer™ medium and prepared for CD28/CD3 activation.

For CD8 cells, a solution of 1 μg/μL aCD28 antibody was added to thecell suspension and plated at 2-3 mL/well in a 6-well plate pre-coatedwith 1 μg/mL aCD3 antibody.

For Treg cells, a solution of 10 pg/mL a CD28 antibody was added to thecell suspension and plated at 2-3 mL/well in a 6-well plate pre-coatedwith 10 pg/mL a CD3 antibody.

The cells were incubated for three (3) days.

Following incubation, the cells were resuspended in fresh CTS™ OpTmizer™medium (ThermoFisher Scientific) at 5×10³ cells/mL and plated at 2-3mL/well in a 6-well plate. The re-plated cells were incubated for two(2) days.

Control and test compounds were added at various concentrations to thecells and incubated at 37° C. for 30 minutes.

The cells were harvested counted, lysed and assayed for pSTAT5activation.

For the resting CD8 T-cells, the EC₅₀ for STAT5 phosphorylation was<10⁻⁸ M.

For activated CD8 T-cells, the EC₅₀ for STAT5 phosphorylation was <10⁻⁸M.

Example 18 STAT5 Phosphorylation in Resting and Activated Human TregCells

The same procedure as described in Example 17 was used to measure STAT5phosphorylation.

For the resting Treg-cells, the EC₅₀ for STAT5 phosphorylation was <10⁻⁸M.

For activated Treg-cells, the EC₅₀ for STAT5 phosphorylation was <10⁻⁸M.

Example 19

IL-2Rα and IL-2Rβ Binding

The expression levels of the IL-2R subunits in TF-1 parental and TF-1βcells was determined using RT-qPCR gene expression profiling. Theresults are presented in Table 6.

TF-1 parental cells and TF-1β cells were incubated with the heterodimerof Example 14 and the STAT5 activation measured as a function ofconcentration. The results are presented in Table 6.

TABLE 6 IL-Rαβγc subunit expression levels and STAT5 activation. TF-1Parental Cells TF-1β Cells IL-2Rα¹ 209 139 IL-2Rβ¹ 1,177 28,685 IL-2Rγc¹18,886 24,511 EC₅₀ (M) ND² <10⁻⁸ ¹Relative expression level: normalizedto GAPDH = 1 × 10⁶ copies; REL = 1E⁶ × 2^((Ctgapdh−Cttarget)) ² Notdetermined.

For the TF-1 parental cells, STAT5 was not activated.

For activated Treg-cells, the EC₅₀ for STAT5 phosphorylation was <10⁻⁸M.

These results demonstrate that the activity of the heterodimer ofExample 14 requires the presence of the IL-2Rβ subunit. Also, inseparate experiments it was determined that the activity of theheterodimer of Example 14 was not blocked by IL-2 and IL-15 antibodies.

Example 20 Competitive Binding

Competitive binding assays were performed to characterize the IL-2Rbinding sites for certain IL-2R and to IL-2Rγc ligands.

Representative phage clones displaying peptides from IL-2Rβ ligandfamilies were bound to the extracellular domain (ECD) of IL-2Rβimmobilized in microtiter wells. Phage binding was conducted in thepresence and absence of synthetic test peptides to determine if phagepeptides and test peptides competed for binding to the same sites onIL-2Rβ. Synthetic test peptides were selected to represent peptides fromIL-2Rβ ligand families, as well positive and negative control peptides.IL-2Rβ ligand family sequences and the specific IL-2Rβ ligands evaluatedare provided in Table 7.

TABLE 7 IL-2Rβ ligand families and ligands. Specific IL-2Rβ FamilyIL-2Rβ Ligand SEQ ID SEQ ID Family NOS: NO: Peptide Sequence 1 1-163  58 Y D C R I A Q V G E L C D L 1052-1057 2A 164-182  169N M C L V G D Y W P S C Q I 1058-1060 2A 164-182  170Q I C D V G Q W W P D C Q V 1058-1060 2B 1-163   83C C Y Q A M V G D L C D F C 1052-1057 2C 1028-1043 1084¹C G M A I G D L C M W T 1084 2C 1028-1043 1043 R W G D V G D L L M P L1084 4 1044 1044 R S C Y Y K R P R L W C S E IL-2Rγc 211-233  224D C S M W E G V E L C W Ligand 914-920 1071-1074 1083 ¹Modified peptidehaving SEQ ID NO: 1034 with amino acids -W-T-.

The IL-2Rβ ligands had a binding affinity (IC₅₀) to the IL-2Rβ subunitof less than 10 μM and a binding affinity (IC₅₀) to the IL-2Rγc subunitof greater than 100 μM.

Phage binding to the immobilized IL-2Rβ ECD was detected by stainingwith antibody against phage coat proteins (anti-phage Ab), staining withlabeled secondary antibody against the anti-phage Ab, and scored byreading OD in the microtiter plate optical reader.

The ELISA signal for each phage binding in the presence and absence ofthe test peptides was compared to determine which synthetic peptidescompeted with which phage peptides for binding to the IL-2Rβ subunit.Those peptide pairs which exhibited competitive binding (i.e., crossinhibition) were considered to bind at the same functional site on theIL-2 receptor. The results are presented in Table 8.

TABLE 8 Binding of IL-2Rβ ligands to IL-2R. Phage Clone Peptide SEQ IDNO: Peptide 58 170 83 1034 or 1084 1044 SEQ ID NO: IL-2β Family 1 2A 2B2C 4 58 1 +¹ + + + − 169 2A + + + + − 1042 2C + + + + − 1044 4 −² − −− + 224 IL-2Rγc − − − − − Ligand ¹Peptide competes with phage binding.²Peptide does not compete with phage binding.

The IL-2Rβ ligands did not bind competitively to the binding site of theIL-2Rβ subunit with IL-2.

A similar study was performed to evaluate the binding of IL-2Rγcligands. IL-2Rγc ligand family sequences and the specific IL-2Rγcligands evaluated are provided in Table 9.

TABLE 9 IL-2Rγc ligand families and ligands. Specific IL-2Rγc FamilyIL-2Rγc Ligand SEQ ID SEQ ID Family NOS: NO: Peptide Sequence 1A 194-210 198 K V C E M W G G V L L C W N 904-913 1065- 1070 1A 194-210  202R T C T E W I E N V V L C W V 904-913 1065- 1070 1B 211-233  224D C S M W E G V E L C W 914-920 1071- 1074 2 234-245  236M C W L E W G E W V G S C L 1075- 1076 3 246-254 1051¹D L S D L S T F W L S Q 921-922 1077- 1082 4 265-267  266C P S M L Q G P E R T W V C 932-940 5 941-948  948S L L K C Y N A S T C A S V F IL-2Rβ 1-163   58Y D C R I A Q V G E L C D L Ligand 1052- 1057 ¹Modified ligand havingamino acid SEQ ID NO: 248.

The IL-2Rγc ligands had a binding affinity (IC₅₀) to the IL-2Rγc subunitof less than 10 μM and a binding affinity (IC₅₀) to the IL-2 subunit ofgreater than 100 μM.

The results are presented in Table 10.

TABLE 10 Binding of IL-2Rγc ligands to IL-2R. Phage Clone Peptide SEQ IDNO: Peptide 198 224 236 248 or 1051 266 948 SEQ ID NO: IL-2Rγc Family 1A1B 2 3 4 5 202 1A +¹ + + + + − 224 1B + + + + + − 236 2 + + + + + − 248or 1051 3 + + + + + − 948 5 −² − − − − +  58 IL-2Rβ − − − − − − Ligand¹Peptide competes with phage binding. ²Peptide does not compete withphage binding.

ASPECTS OF THE INVENTION

The invention is further defined by the following aspects.

Aspect 1. An IL-2Rβ ligand, wherein the IL-2Rβ ligand exhibits a bindingaffinity to the human IL-2Rβ subunit of less than 100 μM.

Aspect 2. The IL-2Rβ ligand of aspect 1, wherein the IL-2Rβ ligandcomprises from 5 to 30 amino acids.

Aspect 3. The IL-2Rβ ligand of any one of aspects 1 to 2, wherein theIL-2Rβ ligand exhibits a binding affinity to the human IL-2Rβ subunitfrom 1 μM to 100 μM.

Aspect 4. The IL-2Rβ ligand of any one of aspects 1 to 2, wherein theIL-2Rβ ligand exhibits a binding affinity to the human IL-2Rβ subunitfrom 0.1 μM to 50 μM.

Aspect 5. The IL-2Rβ ligand of any one of aspects 1 to 2, wherein theIL-2Rβ ligand exhibits a binding affinity to the human IL-2Rβ subunit ofless than 100 μM.

Aspect 6. The IL-2Rβ ligand of any one of aspects 1 to 5, wherein theIL-2Rβ ligand exhibits a binding affinity to a mammalian IL-2Rβ subunitof less than 100 μM.

Aspect 7. The IL-2Rβ ligand of any one of aspects 1 to 6, wherein theIL-2Rβ ligand exhibits a binding affinity to each of the human IL-2Rβsubunit and to the human IL-2Rγc subunit of less than 100 μM.

Aspect 8. The IL-2Rβ ligand of any one of aspects 1 to 7, wherein theIL-2Rβ ligand exhibits a binding affinity to the human IL-2Rα (CD25)subunit of greater than 100 μM.

Aspect 9. The IL-2Rβ ligand of any one of aspects 1 to 8, wherein theIL-2Rβ ligand exhibits a binding affinity to the human IL-2Rβ subunitthat is at least 10 times greater than the binding affinity of theIL-2Rβ ligand to the human IL-2Rα subunit.

Aspect 10. The IL-2Rβ ligand of any one of aspects 1 to 9, wherein theIL-2Rβ ligand comprises the amino acid sequence of Formula (1) (SEQ IDNO: 1), the amino acid sequence of Formula (1a) (SEQ ID NO: 2), or theamino acid sequence of Formula (1b) (SEQ ID NO: 3):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—  (1)

—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—  (1a)

—X¹—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—X¹²—  (1b)

wherein, X¹ is selected from A, D, E, F, G, I, K, L, M, N, P, Q, S, T,V, W, and Y; X² is selected from A, C, D, E, F, G, H, K, L, N, P, R, S,T, W, and Y; X³ is selected from A, D, E, F, G, H, M, N, Q, R, S, T, W,and Y; X⁴ is selected from A, D, E, F, G, I, K, L, M, N, Q, R, S, T, V,and Y; X⁵ is selected from A, G, I, Q, S, T, V, and W; X⁶ is selectedfrom A, D, E, G, H, K, L, M, N, P, Q, R, S, T, and V; X⁷ is selectedfrom F, I, K, L, Q, and V; X⁸ is selected from D, F, G, H, M, N, W, andY; X⁹ is selected from A, D, E, M, P, Q, S, T, V, and W; X¹⁰ is selectedfrom D, F, I, L, M, S, T, V, and Y; X¹¹ is selected from D, E, F, H, I,L, M, Q, S, T, V, W, and Y; and X¹² is selected from F, I, L, M, N, S,V, W, and Y.

Aspect 11. The IL-2Rβ ligand of aspect 10, wherein X¹ is selected fromF, I, L, M, and V.

Aspect 12. The IL-2Rβ ligand of any one of aspects 1 to 11, wherein X²is selected from D, E, F, G, H, L, N, P, R, S, T, W, and Y.

Aspect 13. The IL-2Rβ ligand of any one of aspects 1 to 12, wherein X⁵is A.

Aspect 14. The IL-2Rβ ligand of any one of aspects 1 to 13, wherein X⁶is selected from D, E, and Q.

Aspect 15. The IL-2RP ligand of any one of aspects 1 to 14, wherein X⁷is selected from F, I, L, and V.

Aspect 16. The IL-2Rβ ligand of any one of aspects 1 to 15, wherein X⁸is G.

Aspect 17. The IL-2Rβ ligand of any one of aspects 1 to 16, wherein X⁹is selected from D, E, and Q.

Aspect 18. The IL-2Rβ ligand of any one of aspects 1 to 17, wherein X¹⁰is selected from F, I, L, M, V, and Y.

Aspect 19. The IL-2Rβ ligand of any one of aspects 1 to 18, wherein X¹¹is selected from D and E.

Aspect 20. The IL-2Rβ ligand of any one of aspects 1 to 19, wherein X¹²is selected from F, I, L, M, and V.

Aspect 21. The IL-2Rβ ligand of aspect 10, wherein, X¹ is selected fromF, I, L, M, and V; X² is selected from D, E, F, G, H, L, N, P, R, S, T,W, and Y; X³ is selected from A, D, E, F, G, H, M, N, Q, R, S, T, W, andY; X⁴ is selected from A, D, E, F, G, I, K, L, M, N, Q, R, S, T, V, andY; X⁵ is A; X⁶ is selected from D, E, and Q; X⁷ is selected from F, I,L, and V; X⁸ is G; X⁹ is selected from D, E, and Q; X¹⁰ is selected fromF, I, L, M, V, and Y; X¹¹ is selected from D and E; and X¹² is selectedfrom F, I, L, M, and V.

Aspect 22. The IL-2Rβ ligand of any one of aspects 1 to 9, wherein theIL-2Rβ ligand comprises the amino acid sequence of Formula (1) (SEQ IDNO: 1052), the amino acid sequence of Formula (1a) (SEQ ID NO: 1053), orthe amino acid sequence of Formula (1b) (SEQ ID NO: 1054):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—  (1)

—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—  (1a)

—X¹—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—X¹²—  (1b)

-   -   wherein, X¹ is selected from an amino acid X² is selected from        an amino acid; X³ is selected from an amino acid; X⁴ is selected        from an amino acid; X⁵ is selected from an amino acid comprising        a small hydrophobic side chain; X⁶ is selected from an amino        acid; X⁷ is selected from an amino acid comprising a large        hydrophobic side chain; X⁸ is selected from an amino acid        comprising a small hydrophobic side chain; X⁹ is selected from        an amino acid comprising a polar-neutral or an acidic side        chain; X¹⁰ is selected from an amino acid comprising a large        hydrophobic side chain; X¹¹ is selected from an amino acid; and        X¹² is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 23. The IL-2Rβ ligand of aspect 22, wherein, X¹ is selected froman amino acid comprising a large hydrophobic side chain; X² is selectedfrom an amino acid; X³ is selected from an amino acid; X⁴ is selectedfrom an amino acid; X⁵ is selected from an amino acid comprising a smallhydrophobic side chain; X⁶ is selected from an amino acid comprising apolar-neutral or an acidic side chain; X⁷ is selected from an amino acidcomprising a large hydrophobic side chain; X⁸ is selected from an aminoacid comprising a small hydrophobic side chain; X⁹ is selected from anamino acid comprising a polar-neutral or an acidic side chain; X¹⁰ isselected from an amino acid comprising a large hydrophobic side chain;X¹¹ is selected from an amino acid comprising a polar-neutral or anacidic side chain; and X¹² is selected from an amino acid comprising alarge hydrophobic side chain.

Aspect 24. The IL-2Rβ ligand of aspect 22, wherein, X¹ is selected fromI, L, M, V, F, W, and Y; X² is selected from an amino acid; X³ isselected from an amino acid; X⁴ is selected from an amino acid; X⁵ isselected from A, G, P, S, and T; X⁶ is selected from H, N, Q, S, T, Y,D, and E; X⁷ is selected from I, L, M, V, F, W, and Y; X⁸ is selectedfrom A, G, P, S, and T; X⁹ is selected from H, N, Q, S, T, Y, D, and E;X¹⁰ is selected from I, L, M, V, F, W, and Y; X¹¹ is selected from H, N,Q, S, T, Y, D, and E; and X¹² is selected from I, L, M, V, F, W, and Y.

Aspect 25. The IL-2Rβ ligand of aspect 22, wherein, X¹ is selected fromI, L, M, V, F, W, and Y; X² is selected from an amino acid; X³ isselected from an amino acid; X⁴ is selected from an amino acid; X⁵ is A;X⁶ is selected from H, N, Q, S, T, Y, D, and E; X⁷ is selected from I,L, M, V, F, W, and Y; X⁸ is G; X⁹ is selected from H, N, Q, S, T, Y, D,and E; X¹⁰ is selected from I, L, M, V, F, W, and Y; X¹¹ is selectedfrom H, N, Q, S, T, Y, D, and E; and X¹² is selected from I, L, M, V, F,W, and Y.

Aspect 26. The IL-2Rβ ligand of aspect 25, wherein X¹ is selected fromI, L, M, and V.

Aspect 27. The IL-2Rβ ligand of any one of aspects 25 to 26, wherein X²is selected from D and E.

Aspect 28. The IL-2Rβ ligand of any one of aspects 25 to 27, wherein X⁶is selected from Q, E, and D.

Aspect 29. The IL-2Rβ ligand of any one of aspects 25 to 28, wherein X⁷is selected from V, L, and I.

Aspect 30. The IL-2Rβ ligand of any one of aspects 25 to 29, wherein X⁹is selected from E, D, and Q.

Aspect 31. The IL-2Rβ ligand of any one of aspects 25 to 30, wherein X¹⁰is selected from L, V, I, and Y.

Aspect 32. The IL-2Rβ ligand of any one of aspects 25 to 31, wherein X¹¹is selected from D and E.

Aspect 33. The IL-2Rβ ligand of any one of aspects 25 to 32, wherein X¹²is selected from L, I, and F.

Aspect 34. The IL-2Rβ ligand of aspect 25, wherein, X¹ is selected fromL, I, F, and V; X² is selected from D and E; X⁶ is selected from Q, E,and D; X⁷ is selected from V, L, and I; X⁹ is selected from E, D, and Q;X¹⁰ is selected from L, V, I, and Y; X¹¹ is selected from D and E; andX¹² is selected from L, I, and F.

Aspect 35. The IL-2Rβ ligand of aspect 25, wherein, X¹ is selected fromF, I, M, and Y; X² is selected from E, D, and R; X³ is selected from andamino acid; X⁴ is selected from an amino acid; X⁵ is A; X⁶ is selectedfrom A, P, and Q; X⁷ is selected from I and V; X⁸ is G; X⁹ is selectedfrom E and Q; X¹⁰ is selected from I, L, and V; X¹¹ is selected from E,D, and Q; and X¹² is selected from I and L.

Aspect 36. The IL-2Rβ ligand of any one of aspects 1 to 9, wherein theIL-2Rβ ligand comprises an amino acid sequence selected from any one ofSEQ ID NO: 4 to SEQ ID NO: 163:

Aspect 37. The IL-2Rβ ligand of aspect 36, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 4to SEQ ID NO: 163, wherein the amino acid sequence is terminated withamino acids -G-G on the N-terminus, on the C-terminus, or on both the N-and C-termini.

Aspect 38. The IL-2Rβ ligand of any one of aspects 36 to 37, wherein theIL-2Rβ ligand comprises an amino acid sequence selected from any one ofSEQ ID NO: 4 to SEQ ID NO: 163, wherein each amino acid independentlycomprises one or more of the following conservative substitutions: aminoacids having a small hydrophobic side chain comprising alanine (A),glycine (G), proline (P), serine (S), and threonine (T); amino acidshaving a hydroxyl-containing side chain comprising serine (S) orthreonine (T); amino acids having an acidic side chain comprisingaspartate (D) and glutamate (E); amino acids having a polar-neutral sidechain comprising histidine (H), asparagine (N), glutamine (Q), serine(S), threonine (T), and tyrosine (Y); amino acids having a basic sidechain comprising arginine (R), lysine (K), or histidine (H); and aminoacids having a large hydrophobic side chain comprising isoleucine (I),leucine (L), methionine (M), valine (V), phenylalanine (F), tyrosine(Y), or tryptophan (W).

Aspect 39. The IL-2Rβ ligand of any one of aspects 1 to 9, wherein theIL-2Rβ ligand comprises the amino acid sequence of Formula (2) (SEQ IDNO: 164), the amino acid sequence of Formula (2a) (SEQ ID NO: 165), orthe amino acid sequence of Formula (2b) (SEQ ID NO: 166):

—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—  (2)

—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—  (2a)

—X¹³—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—X²⁴—  (2b)

-   -   wherein, X¹³ is selected from A, D, E, G, N, Q, R, and V; X¹⁴ is        selected from E, F, I, L, M, and Q; X¹⁵ is selected from D, G,        L, and N; X¹⁶ is selected from L, P, V, and Y; X¹⁷ is selected        from F, G, and M; X¹⁸ is selected from A, D, N, and Q; X¹⁹ is        selected from F, I, L, S, V, W, and Y; X²⁰ is selected from D        and W; X²¹ is selected from P and Y; X²² is selected from A, D,        Q, and S; X²³ is selected from I, L, Q, W, and Y; and X²⁴ is        selected from E, F, I, L, T, V, and W.

Aspect 40. The IL-2Rβ ligand of aspect 39, wherein X¹⁶ is V.

Aspect 41. The IL-2Rβ ligand of any one of aspects 39 to 40, wherein X¹⁷is G.

Aspect 42. The IL-2Rβ ligand of any one of aspects 39 to 41, wherein X²⁰is W.

Aspect 43. The IL-2Rβ ligand of any one of aspects 39 to 42, wherein X²¹is P.

Aspect 44. The IL-2Rβ ligand of aspect 39, wherein, X¹³ is selected fromE, N, and Q; X¹⁴ is selected from I and M; X¹⁵ is selected from D, L,and N; X¹⁶ is V; X¹⁷ is G; X¹⁸ is selected from D and Q; X¹⁹ is selectedfrom V, W, and Y; X²⁰ is W; X²¹ is P; X²² is selected from D and S; X²³is selected from L and Q; and X²⁴ is selected from I, L, and V.

Aspect 45. The IL-2Rβ ligand of any one of aspects 1 to 9, wherein theIL-2Rβ ligand comprises an amino acid sequence selected from any one ofSEQ ID NO: 167 to SEQ ID NO: 182.

Aspect 46. The IL-2Rβ ligand of aspect 45, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 167to SEQ ID NO: 182, wherein the amino acid sequence is terminated withamino acids -G-G on the N-terminus, on the C-terminus, or on both the N-and C-termini.

Aspect 47. The IL-2Rβ ligand of any one of aspects 45 to 46, wherein theIL-2Rβ ligand comprises an amino acid sequence selected from any one ofSEQ ID NO: 167 to SEQ ID NO: 182, wherein each amino acid independentlycomprises one or more of the following conservative substitutions: aminoacids having a small hydrophobic side chain comprising alanine (A),glycine (G), proline (P), serine (S) and threonine (T); amino acidshaving a hydroxyl-containing side chain comprising serine (S) orthreonine (T); amino acids having an acidic side chain comprisingaspartate (D) and glutamate (E); amino acids having a polar-neutral sidechain comprising histidine (H), asparagine (N), glutamine (Q), serine(S), threonine (T), and tyrosine (Y); amino acids having a basic sidechain comprising arginine (R), lysine (K), or histidine (H); and aminoacids having a large hydrophobic side chain comprising isoleucine (I),leucine (L), methionine (M), valine (V), phenylalanine (F), tyrosine(Y), or tryptophan (W).

Aspect 48. The IL-2Rβ ligand of any one of aspects 1 to 9, wherein theIL-2Rβ ligand comprises the amino acid sequence of Formula (2) (SEQ IDNO: 1058), the amino acid sequence of Formula (2a) (SEQ ID NO: 1059), orthe amino acid sequence of Formula (2b) (SEQ ID NO: 1060):

—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—  (2)

—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—  (2a)

—X¹³—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—X²⁴—  (2b)

-   -   wherein, X¹³ is selected from an amino acid; X¹⁴ is selected        from an amino acid comprising a large hydrophobic side chain;        X¹⁵ is selected from an amino acid; X¹⁶ is selected from an        amino acid comprising a large hydrophobic side chain; X¹⁷ is        selected from an amino acid comprising a small hydrophobic side        chain; X¹⁸ is selected from an amino acid; X¹⁹ is selected from        an amino acid; X²⁰ is selected from an amino acid comprising a        large hydrophobic side chain; X²¹ is selected from an amino acid        comprising a small hydrophobic side chain; X²² is selected from        an amino acid; X²³ is selected from an amino acid; and X²⁴ is        selected from an amino acid comprising a large hydrophobic side        chain.

Aspect 49. The IL-2Rβ ligand of aspect 48, wherein, X¹³ is selected froman amino acid; X¹⁴ is selected from an amino acid comprising a largehydrophobic side chain; X¹⁵ is selected from an amino acid; X¹⁶ isselected from an amino acid comprising a large hydrophobic side chain;X¹⁷ is selected from an amino acid comprising a small hydrophobic sidechain; X¹⁸ is selected from an amino acid comprising a polar-neutral oran acidic side chain; X¹⁹ is selected from an amino acid comprisinglarge hydrophobic or neutral side chain; X²⁰ is selected from an aminoacid comprising a large hydrophobic side chain; X²¹ is selected from anamino acid comprising a small hydrophobic side chain; X²² is selectedfrom an amino acid; X²³ is selected from an amino acid; and X²⁴ isselected from an amino acid comprising a large hydrophobic side chain.

Aspect 50. The IL-2Rβ ligand of aspect 48, wherein, X¹³ is selected froman amino acid; X¹⁴ is selected from I, L, M, V, F, W, and Y; X¹⁵ isselected from D, E, I, L, M, V, F, Y, and W; X¹⁶ is selected from I, L,M, N, V, F, Y, and W; X¹⁷ is selected from A, G, P, S, and T; X¹⁸ isselected from H, N, Q, S, T, Y, D, and E; X¹⁹ is selected from I, L, M,V, F, W, and Y; X²⁰ is selected from I, L, M, N, V, F, Y, and W; X²¹ isselected from A, G, P, S, and T; X²² is selected from an amino acid; X²³is selected from an amino acid; and X²⁴ is selected from I, L, M, V, F,W, and Y.

Aspect 51. The IL-2Rβ ligand of aspect 50, wherein X¹⁴ is selected fromI and M.

Aspect 52. The IL-2Rβ ligand of any one of aspects 50 to 51, wherein X¹⁶is V.

Aspect 53. The IL-2Rβ ligand of any one of aspects 50 to 52, wherein X¹⁷is G.

Aspect 54. The IL-2Rβ ligand of any one of aspects 50 to 53, wherein X¹⁸is selected from D and Q.

Aspect 55. The IL-2Rβ ligand of any one of aspects 50 to 54, wherein X²⁰is W.

Aspect 56. The IL-2Rβ ligand of any one of aspects 50 to 55, wherein X²¹is P.

Aspect 57. The IL-2Rβ ligand of any one of aspects 50 to 56, wherein X²³is selected from F, I, L, and V.

Aspect 58. The IL-2Rβ ligand of aspect 50, wherein, X¹³ is selected froman amino acid; X¹⁴ is selected from I and M; X¹⁵ is selected from anamino acid; X¹⁶ is V; X¹⁷ is G; X¹⁸ is selected from D and Q; X¹⁹ isselected from I, L, M, V, F, W, and Y; X²⁰ is W; X²¹ is P; X²² isselected from an amino acid; X²³ is selected from an amino acid; and X²⁴is selected from F, I, L, and V.

Aspect 59. The IL-2Rβ ligand of any one of aspects 1 to 9, wherein theIL-2Rβ ligand comprises the amino acid sequence of Formula (3) (SEQ IDNO: 183) or the amino acid sequence of Formula (3a) (SEQ ID NO: 184):

—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—  (3)

—X²⁵—C—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—C—X³⁶—  (3a)

-   -   wherein, X²⁵ is selected from an amino acid; X²⁶ is selected        from an amino acid; X²⁷ is selected from I and V; X²⁸ is G; X²⁹        is selected from D, E, and N; X³⁰ is selected from F, L, and Y;        X³¹ is selected from F, I, and V; X³² is selected from D and Q;        X³³ is selected from an amino acid; X³⁴ is selected from an        amino acid; X³⁵ is selected from an amino acid; and X³⁶ is        selected from an amino acid.

Aspect 60. The IL-2Rβ ligand of aspect 59, wherein, X²⁵ is selected fromL, S, T, and Y; X²⁶ is selected from H and Q; X²⁷ is selected from I andV; X²⁸ is G; X²⁹ is selected from D, E, and N; X³⁰ is selected from F,L, and Y; X³¹ is selected from F, I, and V; X³² is selected from D andQ; X³³ is selected from D, L, and W; X³⁴ is selected from G, L, and T;X³⁵ is selected from D, I, and S; and X³⁶ is selected from A and M.

Aspect 61. The IL-2Rβ ligand of any one of aspects 1 to 9, wherein theIL-2Rβ ligand comprises the amino acid sequence of Formula (3) (SEQ IDNO: 1061) or the amino acid sequence of Formula (3a) (SEQ ID NO: 1062):

—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—  (3)

—X²⁵—C—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—C—X³⁶—  (3a)

-   -   wherein, X²⁵ is selected from an amino acid; X²⁶ is selected        from an amino acid; X²⁷ is selected from an amino acid        comprising a large hydrophobic side chain; X²⁸ is selected from        an amino acid comprising a small hydrophobic side chain; X²⁹ is        selected from an amino acid comprising an acidic side chain or a        polar neutral side chain; X³⁰ is selected from an amino acid;        X³¹ is selected from an amino acid; X³² is selected from an        amino acid comprising a polar-neutral side chain or an acidic        side chain; X³³ is selected from an amino acid; X³⁴ is selected        from an amino acid; X³⁵ is selected from an amino acid; and X³⁶        is selected from an amino acid.

Aspect 62. The IL-2Rβ ligand of aspect 61, wherein, X²⁵ is selected froman amino acid; X²⁶ is selected from an amino acid; X²⁷ is selected froman amino acid comprising a large hydrophobic side chain; X²⁸ is selectedfrom an amino acid comprising a small hydrophobic side chain; X²⁹ isselected from an amino acid comprising an acidic side chain or a polarneutral side chain; X³⁰ is selected from an amino acid comprising alarge hydrophobic side chain; X³¹ is selected from an amino acidcomprising a large hydrophobic side chain; X³² is selected from an aminoacid comprising a polar-neutral side chain or an acidic side chain; andX³³ is selected from an amino acid; X³⁴ is selected from an amino acid;X³⁵ is selected from an amino acid; and X³⁶ is selected from an aminoacid.

Aspect 63. The IL-2Rβ ligand of any one of aspects 1 to 9, wherein theIL-2Rβ ligand comprises the amino acid sequence of Formula (3) (SEQ IDNO: 1063) or the amino acid sequence of Formula (3a) (SEQ ID NO: 1064):

—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—  (3)

—X²⁵—C—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—C—X³⁶—  (3a)

-   -   wherein, X²⁵ is selected from an amino acid; X²⁶ is selected        from an amino acid; X²⁷ is selected from I, L, M, V, F, Y, and        W; X²⁸ is selected from A, G, P, S, and T; X²⁹ is selected from        D, E, H, N, Q, S, T, and Y; X³⁰ is selected from I, L, M, V, F,        Y, and W; X³¹ is selected from I, L, M, V, F, Y, and W; X³² is        selected from D, E, H, N, Q, T, and Y; X³³ is selected from an        amino acid; X³⁴ is selected from an amino acid; X³⁵ is selected        from an amino acid; and X³⁶ is selected from an amino acid.

Aspect 64. The IL-2Rβ ligand of aspect 63, wherein X²⁷ is selected fromV and I.

Aspect 65. The IL-2Rβ ligand of any one of aspects 63 to 64, wherein X²⁸is G.

Aspect 67. The IL-2Rβ ligand of any one of aspects 63 to 65, wherein X²⁹is selected from D and E.

Aspect 68. The IL-2RP ligand of any one of aspects 63 to 66, wherein X³⁰is selected from V, L, F, and Y.

Aspect 69. The IL-2Rβ ligand of any one of aspects 63 to 67, wherein X³¹is selected from I, V, and F.

Aspect 69a. The IL-2Rβ ligand of any one of aspects 63 to 68, whereinX³² is selected from Q and D.

Aspect 70. The IL-2Rβ ligand of aspect 63, wherein, X²⁵ is selected froman amino acid; X²⁶ is selected from an amino acid; X²⁷ is selected fromV and I; X²⁸ is G; X²⁹ is selected from D and E; X³⁰ is selected from V,L, F, and Y; X³¹ is selected from I, V, and F; X³² is selected from Qand D; X³³ is selected from an amino acid; X³⁴ is selected from an aminoacid; X³⁵ is selected from an amino acid; and X³⁶ is selected from anamino acid.

Aspect 71. The IL-2Rβ ligand of any one of aspects 1 to 9, wherein theIL-2Rβ ligand comprises an amino acid sequence selected from any one ofSEQ ID NO: 185 to SEQ ID NO: 193.

Aspect 72. The IL-2Rβ ligand of aspect 71, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 185to SEQ ID NO: 193, wherein the amino acid sequence is terminated withamino acids -G-G on the N-terminus, on the C-terminus, or on both the N-and C-termini.

Aspect 73. The IL-2Rβ ligand of any one of aspects 71 to 72, wherein theIL-2Rβ ligand comprises an amino acid sequence selected from any one ofSEQ ID NO: 185 to SEQ ID NO: 193, wherein each amino acid independentlycomprises one or more of the following conservative substitutions: aminoacids having a small hydrophobic side chain comprising alanine (A),glycine (G), proline (P), serine (S) and threonine (T); amino acidshaving a hydroxyl-containing side chain comprising serine (S) orthreonine (T); amino acids having an acidic side chain comprisingaspartate (D) and glutamate (E); amino acids having a polar-neutral sidechain comprising histidine (H), asparagine (N), glutamine (Q), serine(S), threonine (T), and tyrosine (Y); amino acids having a basic sidechain comprising arginine (R), lysine (K), or histidine (H); and aminoacids having a large hydrophobic side chain comprising isoleucine (I),leucine (L), methionine (M), valine (V), phenylalanine (F), tyrosine(Y), or tryptophan (W).

Aspect 74. An IL-2Rγc ligand, wherein the IL-2Rγc ligand exhibits abinding affinity to the human IL-2Rγc subunit of less than 100 μM.

Aspect 75. The IL-2Rγc ligand of aspect 74, wherein the IL-2Rγc ligandcomprises from 5 to 30 amino acids.

Aspect 76. The IL-2Rγc ligand of any one of aspects 74 to 75, whereinthe IL-2Rγc ligand exhibits a binding affinity to the human IL-2Rγcsubunit in a range from 1 pM to 100 μM.

Aspect 77. The IL-2Rγc ligand of any one of aspects 74 to 75, whereinthe IL-2Rγc ligand exhibits a binding affinity to the human IL-2Rγcsubunit in a range from 0.1 μM to 50 μM.

Aspect 78. The IL-2Rγc ligand of any one of aspects 74 to 75, whereinthe IL-2Rγc ligand exhibits a binding affinity to the human IL-2Rγcsubunit of less than 100 μM.

Aspect 79. The IL-2Rγc ligand of any one of aspects 74 to 78, whereinthe IL-2Rγc ligand exhibits a binding affinity to each of the humanIL-2Rβ subunit and to the human IL-2Rγc subunit of less than 100 μM.

Aspect 80. The IL-2Rγc ligand of any one of aspects 74 to 79, whereinthe IL-2Rγc ligand exhibits a binding affinity to the human IL-2Rα(CD25) subunit.

Aspect 81. The IL-2Rγc ligand of any one of aspects 74 to 80, whereinthe IL-2Rγc ligand exhibits a binding affinity to the human IL-2Rγcsubunit that is at least 10 times greater than the binding affinity ofthe IL-2Rγc ligand to the human IL-2Rα subunit.

Aspect 82. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises the amino acid sequence of Formula (4) (SEQID NO: 1067) or the amino acid sequence of Formula (4a) (SEQ ID NO:1068):

—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—  (4)

—X⁵¹—X⁵²—C—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—C—X⁶¹—X⁶²—  (4a)

-   -   wherein, X⁵¹ is selected from G, I, K, L, Q, R, T, and V; X⁵² is        selected from A, E, I, L, R, S, T, V, and W; X⁵³ is selected        from D, E, F, N, Q, S, and T; X⁵⁴ is selected from D, E, I, M,        N, Q, R, and S; X⁵⁵ is selected from D, E, F, S, T, W, and Y;        X⁵⁶ is selected from D, E, F, G, L, M, N, Q, and Y; X⁵⁷ is        selected from E, G, and N; X⁵⁸ is selected from I, P, T, and V;        X⁵⁹ is selected from I, L, M, S, T, and V; X⁶⁰ is selected from        F, I, and L; X⁶¹ is selected from F, T, and W; and X⁶² is        selected from A, E, G, M, L, N, P, Q, S, V, and W.

Aspect 83. The IL-2Rγc ligand of aspect 82, wherein X⁵¹ is selected fromI, L, and V.

Aspect 84. The IL-2Rγc ligand of any one of aspects 82 to 83, whereinX⁵² is selected from S and T.

Aspect 85. The IL-2Rγc ligand of any one of aspects 82 to 84, whereinX⁵³ is selected from D, E, N, and Q.

Aspect 86. The IL-2Rγc ligand of any one of aspects 82 to 85, whereinX⁵⁴ is selected from D, E, N, and Q.

Aspect 87. The IL-2Rγc ligand of any one of aspects 82 to 86, whereinX⁵⁵ is selected from F, W, and Y.

Aspect 88. The IL-2Rγc ligand of any one of aspects 82 to 87, whereinX⁵⁶ is selected from D, E, N, and Q.

Aspect 89. The IL-2Rγc ligand of any one of aspects 82 to 88, whereinX⁵⁷ is G.

Aspect 90. The IL-2Rγc ligand of any one of aspects 82 to 89, whereinX⁵⁸ is selected from I and V.

Aspect 91. The IL-2Rγc ligand of any one of aspects 82 to 90, whereinX⁵⁹ is selected from I, L, M, and V.

Aspect 92. The IL-2Rγc ligand of any one of aspects 82 to 91, whereinX⁶⁰ is selected from F, I, and L.

Aspect 93. The IL-2Rγc ligand of any one of aspects 82 to 92, whereinX⁶¹ is W.

Aspect 94. The IL-2Rγc ligand of any one of aspects 82 to 93, whereinX⁶² is selected from N and Q.

Aspect 95. The IL-2Rγc ligand of aspect 82, wherein, X⁵¹ is selectedfrom I, L, and V; X⁵² is selected from S and T; X⁵³ is selected from D,E, N, and Q; X⁵⁴ is selected from D and N; X⁵⁵ is selected from F, W,and Y; X⁵⁶ is selected from D, E, N, and Q; X⁵⁷ is G; X⁵⁸ is selectedfrom I and V; X⁵⁹ is selected from I, L, M, and V; X⁶⁰ is selected fromF, I, and L; X⁶¹ is W; and X⁶² is selected from N and Q.

Aspect 96. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises an amino acid sequence selected from anyone of SEQ ID NO: 196 to SEQ ID NO: 210.

Aspect 97. The IL-2Rγc ligand of aspect 96, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 196to SEQ ID NO: 210, wherein the amino acid sequence is terminated withamino acids -G-G on the N-terminus, on the C-terminus, or on both the N-and C-termini.

Aspect 98. The IL-2Rβ ligand of any one of aspects 96 to 97, wherein theIL-2Rβ ligand comprises an amino acid sequence selected from any one ofSEQ ID NO: 196 to SEQ ID NO: 210, wherein each amino acid independentlycomprises one or more of the following conservative substitutions: aminoacids having a small hydrophobic side chain comprising alanine (A),glycine (G), proline (P), serine (S) and threonine (T); amino acidshaving a hydroxyl-containing side chain comprising serine (S) orthreonine (T); amino acids having an acidic side chain comprisingaspartate (D) and glutamate (E); amino acids having a polar-neutral sidechain comprising histidine (H), asparagine (N), glutamine (Q), serine(S), threonine (T), and tyrosine (Y); amino acids having a basic sidechain comprising arginine (R), lysine (K), or histidine (H); and aminoacids having a large hydrophobic side chain comprising isoleucine (I),leucine (L), methionine (M), valine (V), phenylalanine (F), tyrosine(Y), or tryptophan (W).

Aspect 99. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises the amino acid sequence of Formula (4) (SEQID NO: 1065) or the amino acid sequence of Formula (4a) (SEQ ID NO:1066):

—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—  (4)

—X⁵¹—X⁵²—C—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—C—X⁶¹—X⁶²—  (4a)

-   -   wherein, X⁵¹ is selected from an amino acid; X⁵² is selected        from an amino acid; X⁵³ is selected from an amino acid        comprising a polar-neutral side chain or an acidic side chain;        X⁵⁴ is selected from an amino acid comprising a polar-neutral        side chain or an acidic side chain; X⁵⁵ is selected from an        amino acid; X⁵⁶ is selected from an amino acid; X⁵⁷ is selected        from an amino acid comprising a small hydrophobic side chain;        X⁵⁸ is selected from an amino acid comprising a large        hydrophobic side chain; X⁵⁹ is selected from an amino acid        comprising a large hydrophobic side chain; X⁶⁰ is selected from        an amino acid comprising a large hydrophobic side chain; X⁶¹ is        selected from an amino acid comprising a large hydrophobic side        chain; and X⁶² is selected from an amino acid.

Aspect 100. The IL-2Rγc ligand of aspect 99, wherein, X⁵¹ is selectedfrom an amino acid comprising a large hydrophobic side chain and a basicside chain; X⁵² is selected from an amino acid comprising ahydroxyl-containing side chain and a large hydrophobic side chain; X⁵³is selected from an amino acid comprising a polar-neutral side chain oran acidic side chain; X⁵⁴ is selected from an amino acid comprising apolar-neutral side chain or an acidic side chain; X⁵⁵ is selected froman amino acid comprising a large hydrophobic side chain; X⁵⁶ is selectedfrom an amino acid comprising a polar-neutral side chain or an acidicside chain; X⁵⁷ is selected from an amino acid comprising a smallhydrophobic side chain; X⁵⁸ is selected from an amino acid comprising alarge hydrophobic side chain; X⁵⁹ is selected from an amino acidcomprising a large hydrophobic side chain; X⁶⁰ is selected from an aminoacid comprising a large hydrophobic side chain; X⁶¹ is selected from anamino acid comprising a large hydrophobic side chain; and X⁶² isselected from an amino acid comprising a polar-neutral side chain.

Aspect 101. The IL-2Rγc ligand of aspect 99, wherein, X⁵¹ is selectedfrom R, K, H, F, I, L, M, V, Y, and W; X⁵² is selected from S, T, F, I,L, M, V, Y, and W; X⁵³ is selected from D, E, H, N, Q, S, T, and Y; X⁵⁴is selected from D, E, H, N, Q, S, T, and Y; X⁵⁵ is selected from F, I,L, M, V, Y, and W; X⁵⁶ is selected from D, E, H, N, Q, S, T, and Y; X⁵⁷is selected from A, G, P, S, and T; X⁵⁸ is selected from F, I, L, M, V,Y, and W; X⁵⁹ is selected from F, I, L, M, V, Y, and W; X⁶⁰ is selectedfrom F, I, L, M, V, Y, and W; X⁶¹ is selected from F, I, L, M, V, Y, andW; and X⁶² is selected from H, N, Q, S, T, and Y.

Aspect 102. The IL-2Rγc ligand of aspect 101, wherein X⁵¹ is selectedfrom I, L, and V.

Aspect 103. The IL-2Rγc ligand of any one of aspects 101 to 102, whereinX⁵² is selected from S and T.

Aspect 104. The IL-2Rγc ligand of any one of aspects 101 to 103, whereinX⁵³ is selected from D, E, and Q.

Aspect 105. The IL-2Rγc ligand of any one of aspects 101 to 104, whereinX⁵⁴ is selected from D, E, and N.

Aspect 106. The IL-2Rγc ligand of any one of aspects 101 to 105, whereinX⁵⁵ is selected from F, Y, and W.

Aspect 107. The IL-2Rγc ligand of any one of aspects 101 to 106, whereinX⁵⁶ is selected from D, E, N, and Q.

Aspect 108. The IL-2Rγc ligand of any one of aspects 101 to 107, whereinX⁵⁷ is G.

Aspect 109. The IL-2Rγc ligand of any one of aspects 101 to 108, whereinX⁵⁸ is selected from I and V.

Aspect 110. The IL-2Rγc ligand of any one of aspects 101 to 109, whereinX⁵⁹ is selected from I, L, M, and V.

Aspect 111. The IL-2Rγc ligand of any one of aspects 101 to 110, whereinX⁶⁰ is selected from F, I, and L.

Aspect 112. The IL-2Rγc ligand of any one of aspects 101 to 111, whereinX⁶¹ is W.

Aspect 113. The IL-2Rγc ligand of any one of aspects 101 to 112, whereinX⁶² is selected from N and Q.

Aspect 114. The IL-2Rγc ligand of aspect 101, wherein, X⁵¹ is selectedfrom I, L, and V; X⁵² is selected from S and T; X⁵³ is selected from D,E, and Q; X⁵⁴ is selected from D, E, and N; X⁵⁵ is selected from F, Y,and W; X⁵⁶ is selected from D, E, N, and Q; X⁵⁷ is G; X⁵⁸ is selectedfrom I and V; X⁵⁹ is selected from I, L, M, and V; X⁶⁰ is selected fromF, I, and L; X⁶¹ is W; and X⁶² is selected from N and Q.

Aspect 115. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises the amino acid sequence of Formula (5) (SEQID NO: 1073) or Formula (5a) (SEQ ID NO: 1074):

—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—  (5)

—X⁷¹—X⁷²—C—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—C—X⁸¹—X⁸²—  (5a)

-   -   wherein, X⁷¹ is selected from I, L, P, Q, R, T, and V; X⁷² is        selected from A, D, E, I, M, R, T, and V; X⁷³ is selected from        E, M, N, Q, S T, V, W, and Y; X⁷⁴ is selected from D, E, F, G,        I, M, R, S, T, and V; X⁷⁵ is selected from F, W, and Y; X⁷⁶ is        selected from D, E, L, N, Q, and S; X⁷⁷ is selected from G; X⁷⁸        is selected from I, M, and V; X⁷⁹ is selected from D, E, N, Q,        and R; X⁸⁰ is selected from F, I, and L; X⁸¹ is selected from I,        L, R, T, W, and Y; and X⁸² is selected from A, F, H, I, L, N, P,        Q, S, T, and W.

Aspect 116. The IL-2Rγc ligand of aspect 115, wherein X⁷¹ is selectedfrom I, L, and V.

Aspect 117. The IL-2Rγc ligand of any one of aspects 115 to 116, whereinX⁷² is selected from A, D, E, I, M, and V.

Aspect 118. The IL-2Rγc ligand of any one of aspects 115 to 117, whereinX⁷³ is selected from E, Q, and N.

Aspect 119. The IL-2Rγc ligand of any one of aspects 115 to 118, whereinX⁷⁴ is selected from D and E.

Aspect 120. The IL-2Rγc ligand of any one of aspects 115 to 119, whereinX⁷⁵ is selected from F, W, and Y.

Aspect 121. The IL-2Rγc ligand of any one of aspects 115 to 120, whereinX⁷⁶ is selected from D, E, L, N, and Q.

Aspect 122. The IL-2Rγc ligand of any one of aspects 115 to 121, whereinX⁷⁷ is G.

Aspect 123. The IL-2Rγc ligand of any one of aspects 115 to 122, whereinX⁷⁸ is selected from I, M, and V.

Aspect 124. The IL-2Rγc ligand of any one of aspects 115 to 123, whereinX⁷⁹ is selected from D, E, Q, and R.

Aspect 125. The IL-2Rγc ligand of any one of aspects 115 to 124, whereinX⁸⁰ is selected from F, I, and L.

Aspect 126. The IL-2Rγc ligand of any one of aspects 115 to 125, whereinX⁸¹ is W.

Aspect 127. The IL-2Rγc ligand of any one of aspects 115 to 126, whereinX⁸² is selected from N and Q.

Aspect 128. The IL-2Rγc ligand of aspect 115, wherein, X⁷¹ is selectedfrom I, L, and V; X⁷² is selected from A, D, E, I, M, and V; X⁷³ isselected from E, Q, and N; X⁷⁴ is selected from D and E; X⁷⁵ is selectedfrom F, W, and Y; X⁷⁶ is selected from D, E, L, N, and Q; X⁷⁷ is G; X⁷⁸is selected from I, M, and V; X⁷⁹ is selected from D, E, Q, and R; X⁸⁰is selected from F, I, and L; X⁸¹ is W; and X⁸ is selected from N and Q.

Aspect 129. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises the amino acid sequence of Formula (5) (SEQID NO: 1071) or Formula (5a) (SEQ ID NO: 1072):

—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—  (5)

—X⁷¹—X⁷²—C—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—C—X⁸¹—X⁸²—  (5a)

-   -   wherein, X⁷¹ is selected from an amino acid; X⁷² is selected        from an amino acid; X⁷³ is selected from an amino acid; X⁷⁴ is        selected from an amino acid; X⁷⁵ is selected from an amino acid        comprising a large hydrophobic side chain; X⁷⁶ is selected from        an amino acid; X⁷⁷ is selected from a small hydrophobic side        chain; X⁷⁸ is selected from an amino acid comprising a large        hydrophobic side chain; X⁷⁹ is selected from an amino acid        comprising a basic side chain, an acidic side chain, or a        polar-neutral side chain; X⁸⁰ is selected from an amino acid        comprising a large hydrophobic side chain; X⁸¹ is selected from        an amino acid comprising a large hydrophobic side chain; and X⁸²        is selected from an amino acid.

Aspect 130. The IL-2Rγc ligand of aspect 129, wherein, X⁷¹ is selectedfrom an amino acid comprising a large hydrophobic side chain; X⁷² isselected from an amino acid comprising an acidic side chain or a largehydrophobic side chain; X⁷³ is selected from an amino acid comprising anacidic side chain, a hydroxyl-containing side chain, or a polar neutralside chain; X⁷⁴ is selected from an amino acid comprising an acidic sidechain, a hydroxyl-containing side chain, or a large hydrophobic sidechain; X⁷⁵ is selected from an amino acid comprising a large hydrophobicside chain; X⁷⁶ is selected from an amino acid comprising an acidic sidechain, a hydroxyl-containing side chain, or a polar neutral side chain;X⁷⁷ is selected from a small hydrophobic side chain; X⁷⁸ is selectedfrom an amino acid comprising a large hydrophobic side chain; X⁷⁹ isselected from an amino acid comprising a basic side chain, an acidicside chain, or a polar-neutral side chain; X⁸⁰ is selected from an aminoacid comprising a large hydrophobic side chain; X⁸¹ is selected from anamino acid comprising a large hydrophobic side chain; and X⁸² isselected from an amino acid comprising a polar neutral side chain.

Aspect 131. The IL-2Rγc ligand of aspect 129, wherein, X⁷¹ is selectedfrom F, I, L, M, V, Y, and W; X⁷² is selected from D, E, F, I, L, M, V,Y, and W; X⁷³ is selected from D, E, S, T, H, N, Q, S, T, and Y; X⁷⁴ isselected from D, E, S, T, F, I, L, M, V, Y, and W; X⁷⁵ is selected fromF, I, L, M, V, Y, and W; X⁷⁶ is selected from D, E, S, T, H, N, Q, S, T,and Y; X⁷⁷ is selected from A, G, P, S, and T; X⁷⁸ is selected from F,I, L, M, V, Y, and W; X⁷⁹ is selected from R, K, H, D, E, H, N, Q, S, T,and Y; X⁸⁰ is selected from F, I, L, M, V, Y, and W; X⁸¹ is selectedfrom F, I, L, M, V, Y, and W; and X⁸² is selected from H, N, Q, S, T,and Y.

Aspect 132. The IL-2Rγc ligand of aspect 131, wherein X⁷¹ is selectedfrom I, L, and V.

Aspect 133. The IL-2Rγc ligand of any one of aspects 131 to 132, whereinX⁷² is selected from D, E, I, M, and V.

Aspect 134. The IL-2Rγc ligand of any one of aspects 131 to 133, whereinX⁷³ is selected from E, N, and Q.

Aspect 135. The IL-2Rγc ligand of any one of aspects 131 to 134, whereinX⁷⁴ is selected from D and E.

Aspect 136. The IL-2Rγc ligand of any one of aspects 131 to 135, whereinX⁷⁵ is selected from F, W, and Y.

Aspect 137. The IL-2Rγc ligand of any one of aspects 131 to 136, whereinX⁷⁶ is selected from D, E, and N.

Aspect 138. The IL-2Rγc ligand of any one of aspects 131 to 137, whereinX⁷⁷ is selected from G.

Aspect 139. The IL-2Rγc ligand of any one of aspects 131 to 138, whereinX⁷⁸ is selected from I, M, and V.

Aspect 140. The IL-2Rγc ligand of any one of aspects 131 to 139, whereinX⁷⁹ is selected from D, E, N, Q, and R.

Aspect 141. The IL-2Rγc ligand of any one of aspects 131 to 140, whereinX⁸⁰ is selected from F, I, and L.

Aspect 142. The IL-2Rγc ligand of any one of aspects 131 to 141, whereinX⁸¹ is W.

Aspect 143. The IL-2Rγc ligand of any one of aspects 131 to 142, whereinX⁸² is selected from N and Q.

Aspect 144. The IL-2Rγc ligand of aspect 131, wherein, X⁷¹ is selectedfrom I, L, and V; X⁷² is selected from D, E, I, M, and V; X⁷³ isselected from E, N, and Q; X⁷⁴ is selected from D and E; X⁷⁵ is selectedfrom F, W, and Y; X⁷⁶ is selected from D, E, and N; X⁷⁷ is selected fromG; X⁷⁸ is selected from I, M, and V; X⁷⁹ is selected from D, E, N, Q,and R; X⁸⁰ is selected from F, I, and L; X⁸¹ is W; and X⁸² is selectedfrom N and Q.

Aspect 145. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises an amino acid sequence selected from anyone of SEQ ID NO: 213 to SEQ ID NO: 233:

Aspect 146. The IL-2Rγc ligand of aspect 145, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 213to SEQ ID NO: 233, wherein the amino acid sequence is terminated withamino acids -G-G on the N-terminus, on the C-terminus, or on both the N-and C-termini.

Aspect 147. The IL-2Rβ ligand of any one of aspects 145 to 146, whereinthe IL-2Rβ ligand comprises an amino acid sequence selected from any oneof SEQ ID NO: 213 to SEQ ID NO: 233, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S) andthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S) or threonine (T); amino acids having an acidicside chain comprising aspartate (D) and glutamate (E); amino acidshaving a polar-neutral side chain comprising histidine (H), asparagine(N), glutamine (Q), serine (S), threonine (T), and tyrosine (Y); aminoacids having a basic side chain comprising arginine (R), lysine (K), orhistidine (H); and amino acids having a large hydrophobic side chaincomprising isoleucine (I), leucine (L), methionine (M), valine (V),phenylalanine (F), tyrosine (Y), or tryptophan (W).

Aspect 148. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises the amino acid sequence of Formula (6) (SEQID NO: 234) or Formula (6a) (SEQ ID NO: 235):

—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰—X¹⁰¹—  (6)

—X⁹¹—X⁹²—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰—X¹⁰¹—X¹⁰²—X¹⁰³—  (6a)

-   -   wherein, X⁹¹ is selected from C, D, E, and L; X⁹² is selected        from C, L, M, R, S, V, and W; X⁹³ is selected from C, D, F, P,        and R; X⁹⁴ is selected from A, D, L, Q, S, and W; X⁹⁵ is        selected from D, E, F, L, and V; X⁹⁶ is selected from A, D, E,        F, G, K, Q, and S; X⁹⁷ is selected from E, L, M, and W; X⁹⁸ is        selected from G, I, L, W, and Y; X⁹⁹ is selected from E, I, R,        T, and V; X¹⁰⁰ is W; X¹⁰¹ is selected from C, A, I, L, P, and V;        X¹⁰² is selected from C, D, G, H; and X¹⁰³ is selected from C,        D, E, H, S, and T.

Aspect 149. The IL-2Rγc ligand of aspect 148, wherein X⁹¹ is selectedfrom D and E.

Aspect 150. The IL-2Rγc ligand of any one of aspects 148 to 149, whereinX⁹² is selected from L, M, R, S, V, and W.

Aspect 151. The IL-2Rγc ligand of any one of aspects 148 to 150, whereinX⁹³ is selected from D and F.

Aspect 152. The IL-2Rγc ligand of any one of aspects 148 to 151, whereinX⁹⁴ is S.

Aspect 153. The IL-2Rγc ligand of any one of aspects 148 to 152, whereinX⁹⁵ is selected from D and E.

Aspect 154. The IL-2Rγc ligand of any one of aspects 148 to 153, whereinX⁹⁶ is selected from D and E.

Aspect 155. The IL-2Rγc ligand of any one of aspects 148 to 154, whereinX⁹⁷ is selected from L, M, and W.

Aspect 156. The IL-2Rγc ligand of any one of aspects 148 to 155, whereinX⁹⁸ is G.

Aspect 157. The IL-2Rγc ligand of any one of aspects 148 to 156, whereinX⁹⁹ is E.

Aspect 158. The IL-2Rγc ligand of any one of aspects 148 to 157, whereinX¹⁰⁰ is W.

Aspect 159. The IL-2Rγc ligand of any one of aspects 148 to 158, whereinX¹⁰¹ is selected from I, L, and V.

Aspect 160. The IL-2Rγc ligand of any one of aspects 148 to 159, whereinX¹⁰² is selected from D and G.

Aspect 161. The IL-2Rγc ligand of any one of aspects 148 to 160, whereinX¹⁰³ is selected from S and T.

Aspect 162. The IL-2Rγc ligand of aspect 148, wherein, X⁹¹ is selectedfrom D and E; X⁹² is selected from L, M, R, S, V, and W; X⁹³ is selectedfrom D and F; X⁹⁴ is S; X⁹⁵ is selected from D and E; X⁹⁶ is selectedfrom D and E; X⁹⁷ is selected from L, M, and W; X⁹⁸ is G; X⁹⁹ is E; X¹⁰⁰is W; X¹⁰¹ is selected from I, L, and V; X¹⁰² is selected from D and G;and X¹⁰³ is selected from S and T.

Aspect 163. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises an amino acid sequence selected from anyone of SEQ ID NO: 236 to SEQ ID NO: 245.

Aspect 164. The IL-2Rγc ligand of aspect 163, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 236to SEQ ID NO: 245, wherein the amino acid sequence is terminated withamino acids -G-G on the N-terminus, on the C-terminus, or on both the N-and C-termini.

Aspect 165. The IL-2Rβ ligand of any one of aspects 163 to 164, whereinthe IL-2Rβ ligand comprises an amino acid sequence selected from any oneof SEQ ID NO: 236 to SEQ ID NO: 245, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S) andthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S) or threonine (T); amino acids having an acidicside chain comprising aspartate (D) and glutamate (E); amino acidshaving a polar-neutral side chain comprising histidine (H), asparagine(N), glutamine (Q), serine (S), threonine (T), and tyrosine (Y); aminoacids having a basic side chain comprising arginine (R), lysine (K), orhistidine (H); and amino acids having a large hydrophobic side chaincomprising isoleucine (I), leucine (L), methionine (M), valine (V),phenylalanine (F), tyrosine (Y), or tryptophan (W).

Aspect 166. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises the amino acid sequence of Formula (6) (SEQID NO: 1075) or Formula (6a) (SEQ ID NO: 1076):

—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰—X¹⁰¹—  (6)

—X⁹¹—X⁹²—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰—X¹⁰¹—X¹⁰²—X¹⁰³—  (6a)

-   -   wherein, X⁹¹ is selected from an amino acid comprising an acidic        side chain or cysteine; X⁹² is selected from an amino acid; X⁹³        is selected from an amino acid comprising an acidic side chain        or large hydrophobic side chain; X⁹⁴ is selected from an amino        acid; X⁹⁵ is selected from an amino acid; X⁹⁶ is selected from        an amino acid; X⁹⁷ is selected from an amino acid comprising a        large hydrophobic side chain; X⁹⁸ is selected from an amino acid        comprising a small hydrophobic side chain or a large hydrophobic        side chain; X⁹⁹ is selected from an amino acid; X¹⁰⁰ is selected        from an amino acid comprising a large hydrophobic side chain;        X¹⁰¹ is selected from an amino acid comprising a large        hydrophobic side chain; X¹⁰² is selected from an amino acid        comprising a small hydrophobic side chain or an acidic side        chain or cysteine; and X¹⁰³ is selected from an amino acid        comprising an acidic side chain or a hydroxyl-containing side        chain or cysteine.

Aspect 167. The IL-2Rγc ligand of aspect 166, wherein, X⁹¹ is selectedfrom an amino acid comprising an acidic side chain; X⁹² is selected froman amino acid; X⁹³ is selected from an amino acid comprising an acidicside chain or large hydrophobic side chain; X⁹⁴ is selected from anamino acid comprising an acidic side chain or a hydroxyl-containing sidechain; X⁹⁵ is selected from an amino acid comprising an acidic sidechain; X⁹⁶ is selected from an amino acid; X⁹⁷ is selected from an aminoacid comprising a large hydrophobic side chain; X⁹⁸ is selected from anamino acid comprising a small hydrophobic side chain or a largehydrophobic side chain; X⁹⁹ is selected from an amino acid comprising anacidic side chain or large hydrophobic side chain; X¹⁰⁰ is selected froman amino acid comprising a large hydrophobic side chain; X¹⁰¹ isselected from an amino acid comprising a large hydrophobic side chain;X¹⁰² is selected from an amino acid comprising a small hydrophobic sidechain or an acidic side chain; and X¹⁰³ is selected from an amino acidcomprising an acidic side chain or a hydroxyl-containing side chain.

Aspect 168. The IL-2Rγc ligand of aspect 166, wherein, X⁹¹ is selectedfrom D and E; X⁹² is selected from an amino acid; X⁹³ is selected fromD, E, F, I, L, M, V, Y, and W; X⁹⁴ is selected from D, E, S, and T; X⁹⁵is selected from D and E; X⁹⁶ is selected from an amino acid; X⁹⁷ isselected from F, I, L, M, V, Y, and W; X⁹⁸ is selected from A, G, P, S,T, F, I, L, M, V, Y, and W; X⁹⁹ is selected from D, E, F, I, L, M, V, Y,and W; X¹⁰⁰ is selected from F, I, L, M, V, Y, and W; X¹⁰¹ is selectedfrom F, I, L, M, V, Y, and W; X¹⁰² is selected from D, E, A, G, P, S,and T; and X¹⁰³ is selected from D, E, S, and T.

Aspect 169. The IL-2Rγc ligand of aspect 168, wherein X⁹¹ is selectedfrom D and E.

Aspect 170. The IL-2Rγc ligand of any one of aspects 168 to 169, whereinX⁹² is selected from an amino acid.

Aspect 171. The IL-2Rγc ligand of any one of aspects 168 to 170, whereinX⁹³ is selected from D and F.

Aspect 172. The IL-2Rγc ligand of any one of aspects 168 to 171, whereinX⁹⁴ is S.

Aspect 173. The IL-2Rγc ligand of any one of aspects 168 to 172, whereinX⁹⁵ is selected from D and E.

Aspect 174. The IL-2Rγc ligand of any one of aspects 168 to 173, whereinX⁹⁶ is selected from an amino acid.

Aspect 175. The IL-2Rγc ligand of any one of aspects 168 to 174, whereinX⁹⁷ is selected from L, M, and W.

Aspect 176. The IL-2Rγc ligand of any one of aspects 168 to 175, whereinX⁹⁸ is G.

Aspect 177. The IL-2Rγc ligand of any one of aspects 168 to 176, whereinX⁹⁹ is E.

Aspect 178. The IL-2Rγc ligand of any one of aspects 168 to 177, whereinX¹⁰⁰ is W.

Aspect 179. The IL-2Rγc ligand of any one of aspects 168 to 178, whereinX¹⁰¹ is selected from I, L, and V.

Aspect 180. The IL-2Rγc ligand of any one of aspects 168 to 179, whereinX¹⁰² is selected from D and G.

Aspect 181. The IL-2Rγc ligand of any one of aspects 168 to 180, whereinX¹⁰³ is selected from S and T.

Aspect 182. The IL-2Rγc ligand of aspect 168, wherein, X⁹¹ is selectedfrom D and E; X⁹² is selected from an amino acid; X⁹³ is selected from Dand F; X⁹⁴ is S; X⁹⁵ is selected from D and E X⁹⁶ is selected from anamino acid; X⁹⁷ is selected from L, M, and W; X⁹⁸ is G; X⁹⁹ is E; X¹⁰⁰is W; X¹⁰¹ is selected from I, L, and V; X¹⁰² is selected from D and G;and X¹⁰³ is selected from S and T.

Aspect 183. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises the amino acid sequence of Formula (7) (SEQID NO: 1079) or Formula (7a) (SEQ ID NO: 1080):

—X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹⁷—X¹¹⁸—  (7)

—X¹¹¹—X¹¹²—X¹¹³—X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹¹⁷—X¹¹⁸—X¹¹⁹—X¹²⁰—X¹²¹—  (7a)

-   -   wherein, X¹¹¹ is selected from D, G, I, and Q; X¹¹² is selected        from D, I, and L; X¹¹³ is selected from G, L, M, R, S, and Y;        X¹¹⁴ is selected from D, E, S, T, and Y; X¹¹⁵ is selected from        E, L, P, and Q; X¹¹⁶ is selected from D, E, L, S, and T X¹¹⁷ is        selected from F, S, and W; X¹¹⁸ is selected from F, N, W, and Y;        X¹¹⁹ is selected from F, I, L, and R; X¹²⁰ is selected from A,        E, L, and S; and X¹²¹ is selected from K, N, Q, and V.

Aspect 184. The IL-2Rγc ligand of aspect 183, wherein X¹¹¹ is selectedfrom D and Q.

Aspect 185. The IL-2Rγc ligand of any one of aspects 183 to 184, whereinX¹¹² is selected from I and L.

Aspect 186. The IL-2Rγc ligand of any one of aspects 183 to 185, whereinX¹¹³ is selected from G, L, M, R, S, and Y.

Aspect 187. The IL-2Rγc ligand of any one of aspects 183 to 186, whereinX¹¹⁴ is L.

Aspect 188. The IL-2Rγc ligand of any one of aspects 183 to 187, whereinX¹¹⁵ is selected from E and Q.

Aspect 189. The IL-2Rγc ligand of any one of aspects 183 to 188, whereinX¹¹⁶ is selected from D and E.

Aspect 190. The IL-2Rγc ligand of any one of aspects 183 to 189, whereinX¹¹⁷ is selected from F and W.

Aspect 191. The IL-2Rγc ligand of any one of aspects 183 to 190, whereinX¹¹⁸ is selected from F, W, and Y.

Aspect 192. The IL-2Rγc ligand of any one of aspects 183 to 191, whereinX¹¹⁹ is selected from F, I, and L.

Aspect 193. The IL-2Rγc ligand of any one of aspects 183 to 192, whereinX¹²⁰ is S.

Aspect 194. The IL-2Rγc ligand of any one of aspects 183 to 193, whereinX¹²¹ is selected from N and Q.

Aspect 195. The IL-2Rγc ligand of aspect 183, wherein, X¹¹¹ is selectedfrom D and Q; X¹¹² is selected from I and L; X¹¹³ is selected from G, L,M, R, S, and Y; X¹¹⁴ is L; X¹¹⁵ is selected from E and Q; X¹¹⁶ isselected from D and E X¹¹⁷ is selected from F and W; X¹¹⁸ is selectedfrom F, W, and Y; X¹¹⁹ is selected from F, I, and L; X¹²⁰ is S; and X¹²¹is selected from N and Q.

Aspect 196. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises an amino acid sequence selected from anyone of SEQ ID NO: 248 to SEQ ID NO: 254 and SEQ ID NO: 1051:

Aspect 197. The IL-2Rγc ligand of aspect 196, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 248to SEQ ID NO: 254 and SEQ ID NO: 1051, wherein the amino acid sequenceis terminated with amino acids -G-G on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 198. The IL-2Rβ ligand of any one of aspects 196 to 197, whereinthe IL-2Rβ ligand comprises an amino acid sequence selected from any oneof SEQ ID NO: 248 to SEQ ID NO: 254 and SEQ ID NO: 1051, wherein eachamino acid independently comprises one or more of the followingconservative substitutions: amino acids having a small hydrophobic sidechain comprising alanine (A), glycine (G), proline (P), serine (S) andthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S) or threonine (T); amino acids having an acidicside chain comprising aspartate (D) and glutamate (E); amino acidshaving a polar-neutral side chain comprising histidine (H), asparagine(N), glutamine (Q), serine (S), threonine (T), and tyrosine (Y); aminoacids having a basic side chain comprising arginine (R), lysine (K), orhistidine (H); and amino acids having a large hydrophobic side chaincomprising isoleucine (I), leucine (L), methionine (M), valine (V),phenylalanine (F), tyrosine (Y), or tryptophan (W).

Aspect 199. The IL-2Rγc ligand of of any one of aspects 74 to 81,wherein the IL-2Rγc ligand comprises the amino acid sequence of Formula(7) (SEQ ID NO: 1077) or Formula (7a) (SEQ ID NO: 1078):

—X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹⁷—X¹¹⁸—  (7)

—X¹¹¹—X¹¹²—X¹¹³—X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹¹⁷—X¹¹⁸—X¹¹⁹—X¹²⁰—X¹²¹—  (7a)

-   -   wherein, X¹¹¹ is selected from an amino acid; X¹¹² is selected        from an amino acid comprising a large hydrophobic side chain or        an acidic side chain; X¹¹³ is selected from an amino acid; X¹¹⁴        is selected from an amino acid comprising an acidic side chain        or a hydroxyl-containing side chain; X¹¹⁵ is selected from an        amino acid; X¹¹⁶ is selected from an amino acid; X¹¹⁷ is        selected from an amino acid comprising a large hydrophobic side        chain; X¹¹⁸ is selected from an amino acid comprising a large        hydrophobic side chain; X¹¹⁹ is selected from an amino acid        comprising a large hydrophobic side chain; X¹²⁰ is selected from        an amino acid; and X²¹ is selected from an amino acid.

Aspect 200. The IL-2Rγc ligand of aspect 199, wherein, X¹¹¹ is selectedfrom an amino acid; X¹¹² is selected from an amino acid comprising alarge hydrophobic side chain or an acidic side chain; X¹¹³ is selectedfrom an amino acid; X¹¹⁴ is selected from an amino acid comprising anacidic side chain or a hydroxyl-containing side chain; X¹¹⁵ is selectedfrom an amino acid comprising a large hydrophobic side chain; X¹¹⁶ isselected from an amino acid comprising an acidic side chain; X¹¹⁷ isselected from an amino acid comprising a large hydrophobic side chain;X¹¹⁸ is selected from an amino acid comprising a large hydrophobic sidechain; X¹¹⁹ is selected from an amino acid comprising a largehydrophobic side chain; X¹²⁰ is selected from an amino acid; and X¹²¹ isselected from an amino acid comprising a polar-neutral side chain.

Aspect 201. The IL-2Rγc ligand of aspect 199, wherein, X¹¹¹ is selectedfrom an amino acid; X¹¹² is selected from D, E, F, I, L, M, V, Y, and W;X¹¹³ is selected from an amino acid; X¹¹⁴ is selected from D, E, S, andT; X¹¹⁵ is selected from F, I, L, M, V, Y, and W; X¹¹⁶ is selected fromD and E; X¹¹⁷ is selected from F, I, L, M, V, Y, and W; X¹¹⁸ is selectedfrom F, I, L, M, V, Y, and W; X¹¹⁹ is selected from F, I, L, M, V, Y,and W; X¹²⁰ is selected from an amino acid; and X¹²¹ is selected from H,N, Q, S, T, and Y.

Aspect 202. The IL-2Rγc ligand of aspect 201, wherein X¹¹¹ is selectedfrom an amino acid.

Aspect 203. The IL-2Rγc ligand of any one of aspects 201 to 202, whereinX¹¹² is selected from I and L.

Aspect 204. The IL-2Rγc ligand of any one of aspects 201 to 203, whereinX¹¹³ is selected from an amino acid.

Aspect 205. The IL-2Rγc ligand of any one of aspects 201 to 204, whereinX¹¹⁴ is selected from D, E, and S.

Aspect 206. The IL-2Rγc ligand of any one of aspects 201 to 205, whereinX¹¹⁵ is L.

Aspect 207. The IL-2Rγc ligand of any one of aspects 201 to 206, whereinX¹¹⁶ is selected from D and E.

Aspect 208. The IL-2Rγc ligand of any one of aspects 201 to 207, whereinX¹¹⁷ is selected from F and W.

Aspect 209. The IL-2Rγc ligand of any one of aspects 201 to 208, whereinX¹¹⁸ is selected from F, W and Y.

Aspect 210. The IL-2Rγc ligand of any one of aspects 201 to 209, whereinX¹¹⁹ is selected from F, I, and L.

Aspect 211. The IL-2Rγc ligand of any one of aspects 201 to 210, whereinX¹²⁰ is selected from an amino acid.

Aspect 212. The IL-2Rγc ligand of any one of aspects 201 to 211, whereinX¹²¹ is selected from Q and N.

Aspect 213. The IL-2Rγc ligand of aspect 201, wherein, X¹¹¹ is selectedfrom an amino acid; X¹¹² is selected from I and L; X¹¹³ is selected froman amino acid; X¹¹⁴ is selected from D, E, and S; X¹¹⁵ is L; X¹¹⁶ isselected from D and E; X¹¹⁷ is selected from F and W; X¹¹⁸ is selectedfrom F, W and Y; X¹¹⁹ is selected from F, I, and L; X¹²⁰ is selectedfrom an amino acid; and X¹²¹ is selected from Q and N.

Aspect 214. The IL-2Rγc ligand of any one of aspects 74 to 81, whereinthe IL-2Rγc ligand comprises an amino acid sequence selected from anyone of SEQ ID NO: 255 to SEQ ID NO: 267:

Aspect 215. The IL-2Rγc ligand of aspect 214, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 255to SEQ ID NO: 267, wherein the amino acid sequence is terminated withamino acids -G-G on the N-terminus, on the C-terminus, or on both the N-and C-termini.

Aspect 216. The IL-2Rβ ligand of any one of aspects 214 to 215, whereinthe IL-2Rβ ligand comprises an amino acid sequence selected from any oneof SEQ ID NO: 255 to SEQ ID NO: 267, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S) andthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S) or threonine (T); amino acids having an acidicside chain comprising aspartate (D) and glutamate (E); amino acidshaving a polar-neutral side chain comprising histidine (H), asparagine(N), glutamine (Q), serine (S), threonine (T), and tyrosine (Y); aminoacids having a basic side chain comprising arginine (R), lysine (K), orhistidine (H); and amino acids having a large hydrophobic side chaincomprising isoleucine (I), leucine (L), methionine (M), valine (V),phenylalanine (F), tyrosine (Y), or tryptophan (W).

Aspect 217. A pH-selective IL-2Rβ ligand comprising an amino acidsequence selected from a ligand having SEQ ID NO: 400 to SEQ ID NO: 577.

Aspect 218. The pH-selective IL-2Rβ ligand of aspect 217, wherein thepH-selective IL-2Rβ ligand exhibits a greater than 15% decrease inbinding to the IL-2Rβ receptor at pH 7.5 compared to pH 6.0.

Aspect 219. The pH-selective IL-2Rβ ligand of aspect 518, wherein theligand comprises an amino acid sequence selected from a ligand havingSEQ ID: NOS: 400, 402-405, 407, 409, 410, 411, 413, 415, 416, 418, 419,420, 421, 423, 425-432, 436, 438-440, 442-446, 448, 450, 452, 453-456,459-461, 463-468, 470, 471, 473-477, 479, 481-486, 489, 491, 493-496,498-507, 510-519, 521-524, 526-531, 534-537, 543, 545-548, 550, 551,558-564, 566, 568-573, and 575, wherein the pH-selective binding isdetermined as described in Examples 9-12.

Aspect 220. The pH-selective IL-2Rβ ligand of aspect 217, wherein thepH-selective IL-2Rβ ligand exhibits a greater than 50% decrease inbinding to the IL-2Rβ receptor at pH 7.5 compared to pH 6.0.

Aspect 221. The pH-selective IL-2Rβ ligand of aspect 520, wherein theligand comprises an amino acid sequence selected from a ligand havingSEQ ID: NOS: 400, 404-405, 407, 409, 410, 413, 415, 420, 426, 431, 432,438-440, 442, 444-446, 450, 452, 453, 455, 459, 464-467, 473-475, 479,480, 482-484, 486, 489, 493, 496, 498, 502, 504, 510-514, 516-519,521-523, 527-530, 537, 543, 545-547, 550, 558-564, 571-573, and 575,where the pH-selective binding is determined as described in Examples9-12.

Aspect 222. The pH-selective IL-2Rβ ligand of any one of aspects 217 to221, wherein the pH-selective IL-2Rβ ligand comprises an amino acidsequence selected from any one of SEQ ID NO: 400 to SEQ ID NO: 577,wherein the amino acid sequence is terminated with amino acids -G-G onthe N-terminus, on the C-terminus, or on both the N- and C-termini.

Aspect 223. The pH-selective IL-2Rβ ligand of any one of aspects 217 to222, wherein the pH-selective IL-2Rβ ligand an amino acid sequenceselected from any one of SEQ ID NO: 400 to SEQ ID NO: 577, wherein eachamino acid independently comprises one or more of the followingconservative substitutions: amino acids having a small hydrophobic sidechain comprising alanine (A), glycine (G), proline (P), serine (S) andthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S) or threonine (T); amino acids having an acidicside chain comprising aspartate (D) and glutamate (E); amino acidshaving a polar-neutral side chain comprising histidine (H), asparagine(N), glutamine (Q), serine (S), threonine (T), and tyrosine (Y); aminoacids having a basic side chain comprising arginine (R), lysine (K), orhistidine (H); and amino acids having a large hydrophobic side chaincomprising isoleucine (I), leucine (L), methionine (M), valine (V),phenylalanine (F), tyrosine (Y), or tryptophan (W).

Aspect 224. The pH-selective IL-2Rβ ligand of any one of aspects 217 to223, wherein the pH-selective IL-2Rβ ligand comprises from 5 to 30 aminoacids.

Aspect 225. The pH-selective IL-2Rβ ligand of any one of aspects 217 to224, wherein the pH-selective IL-2Rβ ligand exhibits a binding affinity(IC₅₀) to the human IL-2Rβ subunit at pH 6.0 from 1 pM to 100 μM.

Aspect 226. The pH-selective IL-2Rβ ligand of any one of aspects 217 to224, wherein the pH-selective IL-2Rβ ligand exhibits a binding affinity(IC₅₀) to the human IL-2Rβ subunit at pH 6.0 from 0.1 μM to 50 μM.

Aspect 227. The pH-selective IL-2Rβ ligand of any one of aspects 217 to224, wherein the pH-selective IL-2Rβ ligand exhibits a binding affinity(IC₅₀) to the human IL-2Rβ subunit at pH 6.0 of less than 100 μM.

Aspect 228. The pH-selective IL-2Rβ ligand of any one of aspects 217 to224, wherein the pH-selective IL-2Rβ ligand exhibits a binding affinity(IC₅₀) to a mammalian IL-2Rβ subunit at pH 6.0 of less than 100 μM.

Aspect 229. The pH-selective IL-2Rβ ligand of any one of aspects 217 to228, wherein the pH-selective IL-2Rβ ligand exhibits a binding affinity(IC₅₀) to each of the human IL-2Rβ subunit and to the human IL-2Rγcsubunit of less than 100 μM.

Aspect 230. The pH-selective IL-2Rβ ligand of any one of aspects 217 to229, wherein the pH-selective IL-2Rβ ligand exhibits a binding affinity(IC₅₀) to the human IL-2Rα (CD25) subunit of greater than 100 μM.

Aspect 231. The pH-selective IL-2Rβ ligand of any one of aspects 217 to230, wherein the pH-selective IL-2Rβ ligand exhibits a binding affinity(IC₅₀) to the human IL-2Rβ subunit that is at least 10 times greaterthan the binding affinity (IC₅₀) of the IL-2Rβ ligand to the humanIL-2Rα subunit.

Aspect 232. A compound comprising: an IL-2Rβ ligand of any one ofaspects 1 to 73 and 217 t0 231; an IL-2Rγc ligand of any one of aspects74 to 216; or an IL-2Rβ ligand of any one of aspects 1 to 73 and anIL-2Rγc ligand of any one of aspects 74 to 216.

Aspect 233. The compound of aspect 232, wherein the compound is selectedfrom a peptide, a conjugate, a fusion protein, and a single chainpeptide.

Aspect 234. The compound of aspect 233, wherein the compound is apeptide.

Aspect 235. The compound of aspect 234, wherein the peptide has amolecular weight within a range from 500 Daltons to 15,000 Daltons.

Aspect 236. The compound of any one of aspects 234 to 235, wherein thepeptide comprises from 5 to 5,000 amino acids.

Aspect 237. The compound of aspect 233, wherein the compound comprises aconjugate.

Aspect 238. The compound of aspect 237, wherein the conjugate comprisesat least one IL-2Rβ ligand.

Aspect 239. The compound of aspect 237, wherein the conjugate comprises:at least two IL-2Rβ ligands; and at least one linker attached to each ofthe at least two IL-2Rβ ligands.

Aspect 240. The compound of any one of aspects 237 to 239, wherein theconjugate comprises a least one IL-2Rγc ligand.

Aspect 241. The compound of aspect 237, wherein the conjugate comprises:at least two IL-2Rγc ligands; and at least one linker attached to eachof the at least two IL-2Rγc ligands.

Aspect 242. The compound of aspect 237, wherein the conjugate comprises:at least one IL-2Rβ ligand; at least one IL-2Rγc ligand; and at leastone linker attached to the at least one IL-2Rβ ligand and to the atleast one IL-2Rγc ligand.

Aspect 243. The compound of any one of aspects 237 to 228, wherein theconjugate comprises at least one moiety, amino acid, or polypeptideconfigured to modify a property of the conjugate.

Aspect 244. The compound of aspect 243, wherein the property is selectedfrom aqueous solubility, polarity, lipophilicity, pharmacokineticprofile, targeting, bioavailability, pH-dependent binding, and caging(reversible incapacitation).

Aspect 245. The compound of any one of aspects 243 to 244, wherein theat least one moiety is cleavable in vivo.

Aspect 246. The compound of any one of aspects 243 to 245, wherein theat least one moiety comprises an irreversibly cleavable promoiety.

Aspect 247. The compound of aspect 246, wherein the promoiety isconfigured to be releasable in a target-specific environment.

Aspect 248. The compound of aspect 247, wherein the target-specificenvironment comprises an enzyme, pH, or a combination thereof.

Aspect 249. The compound of aspect 248, wherein the moiety comprises apolymer, a peptide, an antibody, or a combination of any of theforegoing

Aspect 250. The compound of aspect 243, comprising a pharmacokineticmoiety.

Aspect 251. The compound of aspect 250, wherein the pharmacokineticmoiety comprises a polyethylene glycol.

Aspect 252. The compound of aspect 243, comprising a tumor-targetingmoiety.

Aspect 253. The compound of aspect 252, wherein the tumor-targetingmoiety comprises a tumor-specific antibody, a tumor-specific antibodyfragment, a tumor-specific protein, a tumor-specific peptide, or acombination of any of the foregoing.

Aspect 254. The compound of aspect 232, comprising a linker covalentlybound to the IL-2Rβ ligand, an IL-2Rγc ligand, or a combination thereof.

Aspect 255. The compound of aspect 254, wherein the linker is a peptidehaving from 5 to 50 amino acids.

Aspect 256. The compound of aspect 254, wherein the linker comprises apolyethylene glycol.

Aspect 257. The compound of aspect 232, wherein the compound comprises aheterodimer, wherein the heterodimer comprises: an IL-2Rβ ligand; anIL-2Rγc ligand; and a linker; wherein each of the IL-2Rβ ligand and theIL-2Rγc ligand comprise an amino-terminus (N-terminus), a carboxyterminus (C-terminus), and an amino acid side chain; wherein the IL-2Rβligand is attached to the linker through the amino-terminus(N-terminus), the carboxy terminus (C-terminus), an amino acid sidechain, or a combination of any of the foregoing; and wherein the IL-2Rγcligand is attached to the linker through the amino-terminus(N-terminus), the carboxy terminus (C-terminus), an amino acid sidechain, or a combination of any of the foregoing.

Aspect 258. The compound of aspect 232, wherein the conjugate comprisesa heterodimer, wherein the heterodimer comprises: an IL-2Rβ ligand; anIL-2Rγc ligand; and a linker; wherein each of the IL-2Rβ ligand and theIL-2Rγc ligand comprise an amino-terminus (N-terminus) and a carboxyterminus (C-terminus); and wherein each of the IL-2Rβ ligand and theIL-2Rγc ligand is covalently bound to the linker.

Aspect 259. The compound of aspect 258, wherein each of the IL-2Rβligand and the IL-2Rγc ligand is covalently bound to the linker throughthe respective C-termini.

Aspect 260. The compound of aspect 258, wherein, the N-terminus of theIL-2Rβ ligand is covalently bound to the linker; and the C-terminus ofthe IL-2Rγc ligand is covalently bound to the linker.

Aspect 261. The compound of aspect 258, wherein, the C-terminus of theIL-2Rβ ligand is covalently bound to the linker; and the N-terminus ofthe IL-2Rγc ligand is covalently bound to the linker.

Aspect 262. The compound of aspect 258, wherein, the IL-2Rβ ligand iscovalently bound to the linker through an amino acid side chain; and theIL-2Rγc ligand is covalently bound to the linker through an amino acidside chain.

Aspect 263. The compound of aspect 258, wherein, the IL-2Rβ ligand iscovalently bound to the linker through an amino acid side chain, throughthe C-terminus, or through the N-terminus; and the IL-2Rγc ligand iscovalently bound to the linker through an amino acid side chain, throughthe C-terminus, or through the N-terminus.

Aspect 264. The compound of aspect 258, wherein the heterodimer isconfigured to activate the IL-2 receptor.

Aspect 265. The compound of aspect 258, wherein the linker is configuredsuch that the heterodimer activates the IL-2 receptor.

Aspect 266. The compound of any one of aspects 258 to 265, wherein, whenincubated with the heterodimer, primary human peripheral bloodmononuclear cells (PBMC) expressing the human IL-2Rβγc subunit,phosphorylate transcription 5 (STAT5).

Aspect 267. The compound of any one of aspects 258 to 266, wherein, whenincubated with the heterodimer, primary human peripheral bloodmononuclear cells (PBMC) expressing the human IL-2Rα [CD25] subunit, donot phosphorylate transcription 5 (STAT5).

Aspect 268. The compound of any one of aspects 258 to 267, wherein theheterodimer comprises a conformation configured to activate humanIL-2Rβγc signaling pathways.

Aspect 269. The compound of aspect 232, wherein the compound comprises asingle chain peptide.

Aspect 270. The compound of aspect 269, wherein the single chain peptidecomprises at least one IL-2Rβ ligand.

Aspect 271. The compound of aspect 269, wherein the single chain peptidecomprises: at least two IL-2Rβ ligands; and at least one linker attachedto the at least two IL-2Rβ ligands.

Aspect 272. The compound of aspect 269, wherein the single chain peptidecomprises a least one IL-2Rγc ligand.

Aspect 273. The compound of aspect 269, wherein the single chain peptidecomprises: at least two IL-2Rγc ligands; and at least one linkerattached to the at least two IL-2Rγc ligands.

Aspect 274. The compound of aspect 269, wherein the single chain peptidecomprises: at least one IL-2Rβ ligand; at least one IL-2Rγc ligand; andat least one linker attached to the at least one IL-2Rβ ligand and tothe at least one IL-2Rγc ligand.

Aspect 275. The compound of aspect 232, wherein the compound is a fusionprotein.

Aspect 276. The compound of aspect 275, wherein the fusion proteincomprises: an IL-2Rβ ligand; an IL-2Rγc ligand; and a peptide linkerdomain, wherein the peptide linker domain is bound to the IL-2Rβ ligandand to the IL-2Rγc ligand.

Aspect 277. The compound of aspect 275, wherein, each domain has anamino-terminus (N-terminus) and a carboxy terminus (C-terminus); andwherein the fusion protein is configured so that the C-terminus and thehuman IL-2 variant protein domain is fused through a peptide bond to theN-terminus of the peptide linker domain, and the N-terminus of thepeptide linker domain, and the N-terminus of the IgG Fc protein domainis fused through a peptide bond to the C-terminus of the peptide linkerdomain.

Aspect 278. A nucleic acid encoding the fusion protein of aspect 275.

Aspect 279. The compound of aspect 232, wherein the compound comprises alabel.

Aspect 280. The compound of aspect 279, wherein the label is selectedfrom a radioisotope, a fluorophore, or a combination thereof.

Aspect 281. The compound of aspect 232, wherein the compound comprises acage to protect peripheral tissues for the toxicity of IL-2R activation.

Aspect 282. The compound of aspect 232, wherein the compound comprises aprodrug.

Aspect 283. The compound of aspect 282, wherein the compound comprises amoiety configured to sustain a circulating reservoir of the prodrug.

Aspect 284. The compound of aspect 232, wherein the compound comprises amoiety configured to target the IL-2R-directed immuno-stimulation of theeffector immune cells in the tumor.

Aspect 285. A pharmaceutical composition comprising; the IL-2Rβ ligandof any one of aspects 1 to 73 and 217 to 231; the IL-2Rγc ligand of anyone of aspects 74 to 216; the compound of any one of aspects 232 to 284;or a combination of any of the foregoing.

Aspect 286. A method of treating cancer in a patient, comprisingadministering to a patient in need of such treatment, a therapeuticallyeffective amount of the pharmaceutical composition of aspect 270.

Aspect 287. A method of treating cancer in a patient, comprisingadministering to a patient in need of such treatment, a therapeuticallyeffective amount of; the IL-2Rβ ligand of any one of aspects 1 to 73 and217 to 231; the IL-2Rγc ligand of any one of aspects 74 to 216; thecompound of any one of aspects 232 to 284; or a combination of any ofthe foregoing.

Aspect 288. The method of aspect 287, wherein the cancer comprises asolid tumor.

Aspect 289. A method of treating an autoimmune disease in a patient,comprising administering to a patient in need of such treatment, atherapeutically effective amount of the pharmaceutical composition ofaspect 285.

Aspect 290. A method of treating an autoimmune disease in a patient,comprising administering to a patient in need of such treatment, atherapeutically effective amount of; the IL-2Rβ ligand of any one ofaspects 1 to 73 and 217 to 231; the IL-2Rγc ligand of any one of aspects74 to 216; the compound of any one of aspects 232 to 284; or acombination of any of the foregoing.

Aspect 291. A method of screening compounds for IL-2 receptor activity,comprising: contacting a cell with, the IL-2Rβ ligand of any one ofaspects 1 to 73 and 217 to 231; the IL-2Rγc ligand of any one of aspects74 to 216; the compound of any one of aspects 232 to 284; or acombination of any of the foregoing; wherein the cell expresses the IL-2receptor; and contacting the cell with a test compound; and determiningthe activity of the test compound.

Aspect 292. A method of activating the human IL-2Rβ subunit, the humanIL-2Rγc subunit, or both the human IL-2Rβ subunit and the human IL-2Rγcsubunit, comprising contacting a cell expressing the IL-2 receptor invivo with: the IL-2Rβ ligand of any one of aspects 1 to 73 and 217 to231; the IL-2Rγc ligand of any one of aspects 74 to 216; the compound ofany one of aspects 232 to 284; or a combination of any of the foregoing.

Aspect 293. A method of activating the human IL-2Rβ subunit and thehuman IL-2Rγc subunit in a patient, comprising administering to apatient an effective amount of: the IL-2Rβ ligand of any one of aspects1 to 73 and 217 to 231; the IL-2Rγc ligand of any one of aspects 74 to216; the compound of any one of aspects 232 to 284; or a combination ofany of the foregoing.

Aspect 294. A method of treating a disease in a patient, wherein theIL-2 receptor signaling pathway is associated with the etiology of thedisease, comprising administering to a patient in need of such treatmenta therapeutically effective amount of: the IL-2Rβ ligand of any one ofaspects 1 to 73 and 217 to 231; the IL-2Rγc ligand of any one of aspects74 to 216; the compound of any one of aspects 232 to 284; or acombination of any of the foregoing.

Aspect 295. A method of treating a disease in a patient, whereinactivation of the IL-2 receptor is effective in treating the disease,comprising administering to a patient in need of such treatment atherapeutically effective amount of: the IL-2Rβ ligand of any one ofaspects 1 to 73 and 217 to 231; the IL-2Rγc ligand of any one of aspects74 to 216; the compound of any one of aspects 232 to 284; or acombination of any of the foregoing.

Aspect 1A. An IL-2Rβ ligand, wherein the IL-2Rβ ligand exhibits abinding affinity (IC₅₀) to the human IL-2Rβ subunit of less than 100 pM.

Aspect 2A. The IL-2Rβ ligand of aspect 1A, wherein the IL-2Rβ ligandcomprises from 5 to 30 amino acids.

Aspect 3A. The IL-2Rβ ligand of any one of aspects 1A to 2A, wherein theIL-2Rβ ligand exhibits a binding affinity (IC₅₀) to the human IL-2Rβsubunit from 1 pM to 100 pM.

Aspect 4A. The IL-2Rβ ligand of any one of aspects 1A to 2A, wherein theIL-2Rβ ligand exhibits a binding affinity (IC₅₀) to the human IL-2Rβsubunit from 0.1 μM to 50 μM.

Aspect 5A. The IL-2Rβ ligand of any one of aspects 1A to 2A, wherein theIL-2Rβ ligand exhibits a binding affinity (IC₅₀) to the human IL-2Rβsubunit of less than 100 μM.

Aspect 6A. The IL-2Rβ ligand of any one of aspects 1A to 2A, wherein theIL-2Rβ ligand exhibits a binding affinity (IC₅₀) to a mammalian IL-2Rβsubunit of less than 100 μM.

Aspect 7A. The IL-2Rβ ligand of any one of aspects 1A to 6A, wherein theIL-2Rβ ligand exhibits a binding affinity (IC₅₀) to each of the humanIL-2Rβ subunit and to the human IL-2Rγc subunit of less than 100 μM.

Aspect 8A. The IL-2Rβ ligand of any one of aspects 1A to 7A, wherein theIL-2Rβ ligand exhibits a binding affinity (IC₅₀) to the human IL-2Rα(CD25) subunit of greater than 100 μM.

Aspect 9A. The IL-2Rβ ligand of any one of aspects 1A to 7A, wherein theIL-2Rβ ligand exhibits a binding affinity (IC₅₀) to the human IL-2Rβsubunit that is at least 10 times greater than the binding affinity(IC₅₀) of the IL-2Rβ ligand to the human IL-2Rα subunit.

Aspect 10A. The IL-2Rβ ligand of any one of aspects 1A to 9A, whereinthe IL-2Rβ ligand comprises the amino acid sequence of Formula (1) (SEQID NO: 1), the amino acid sequence of Formula (1a) (SEQ ID NO: 2), orthe amino acid sequence of Formula (1b) (SEQ ID NO: 3):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—  (1)

—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—  (1a)

—X¹—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—X¹²—  (1b)

-   -   wherein, X¹ is selected from A, D, E, F, G, I, K, L, M, N, P, Q,        S, T, V, W, and Y; X² is selected from A, C, D, E, F, G, H, K,        L, N, P, R, S, T, W, and Y; X³ is selected from A, D, E, F, G,        H, M, N, Q, R, S, T, W, and Y; X⁴ is selected from A, D, E, F,        G, I, K, L, M, N, Q, R, S, T, V, and Y; X⁵ is selected from A,        G, I, Q, S, T, V, and W; X⁶ is selected from A, D, E, G, H, K,        L, M, N, P, Q, R, S, T, and V; X⁷ is selected from F, I, K, L,        Q, and V; X⁸ is selected from D, F, G, H, M, N, W, and Y; X⁹ is        selected from A, D, E, M, P, Q, S, T, V, and W; X¹⁰ is selected        from D, F, I, L, M, S, T, V, and Y; X¹¹ is selected from D, E,        F, H, I, L, M, Q, S, T, V, W, and Y; and X¹² is selected from F,        I, L, M, N, S, V, W, and Y.

Aspect 11A. The IL-2Rβ ligand of aspect 10A, wherein X¹ is selected fromF, I, L, M, and V.

Aspect 12A. The IL-2Rβ ligand of any one of aspects 10A to 11A, whereinX² is selected from D, E, F, G, H, L, N, P, R, S, T, W, and Y.

Aspect 13A. The IL-2Rβ ligand of any one of aspects 10A to 12A, whereinX⁵ is A.

Aspect 14A. The IL-2Rβ ligand of any one of aspects 10A to 13A, whereinX⁶ is selected from D, E, and Q.

Aspect 15A. The IL-2Rβ ligand of any one of aspects 10A to 14A, whereinX⁷ is selected from F, I, L, and V.

Aspect 16A. The IL-2Rβ ligand of any one of aspects 10A to 15A, whereinX⁸ is G.

Aspect 17A. The IL-2Rβ ligand of any one of aspects 10A to 16A, whereinX⁹ is selected from D, E, and Q.

Aspect 18A. The IL-2Rβ ligand of any one of aspects 10A to 17A, whereinX¹⁰ is selected from F, I, L, M, V, and Y.

Aspect 19A. The IL-2Rβ ligand of any one of aspects 10A to 18A, whereinX¹¹ is selected from D and E.

Aspect 20A. The IL-2Rβ ligand of any one of aspects 10A to 19A, whereinX¹² is selected from F, I, L, M, and V.

Aspect 21A. The IL-2Rβ ligand of aspect 10A, wherein, X¹ is selectedfrom F, I, L, M, and V; X² is selected from D, E, F, G, H, L, N, P, R,S, T, W, and Y; X³ is selected from A, D, E, F, G, H, M, N, Q, R, S, T,W, and Y; X⁴ is selected from A, D, E, F, G, I, K, L, M, N, Q, R, S, T,V, and Y; X⁵ is A; X⁶ is selected from D, E, and Q; X⁷ is selected fromF, I, L, and V; X⁸ is G; X⁹ is selected from D, E, and Q; X¹⁰ isselected from F, I, L, M, V, and Y; X¹¹ is selected from D and E; andX¹² is selected from F, I, L, M, and V.

Aspect 22A. The IL-2Rβ ligand of any one of aspects 1A to 9A, whereinthe IL-2Rβ ligand comprises the amino acid sequence of Formula (1) (SEQID NO: 1052), the amino acid sequence of Formula (1a) (SEQ ID NO: 1053),or the amino acid sequence of Formula (1b) (SEQ ID NO: 1054):

—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—  (1)

—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—  (1a)

—X¹—X²—C—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—C—X¹¹—X¹²—  (1b)

-   -   wherein, X¹ is selected from an amino acid; X² is selected from        an amino acid; X³ is selected from an amino acid; X⁴ is selected        from an amino acid; X⁵ is selected from an amino acid comprising        a small hydrophobic side chain; X⁶ is selected from an amino        acid; X⁷ is selected from an amino acid comprising a large        hydrophobic side chain; X⁸ is selected from an amino acid        comprising a small hydrophobic side chain; X⁹ is selected from        an amino acid comprising a polar-neutral or an acidic side        chain; X¹⁰ is selected from an amino acid comprising a large        hydrophobic side chain; X¹¹ is selected from an amino acid; and        X¹² is selected from an amino acid comprising a large        hydrophobic side chain.

Aspect 23A. The IL-2Rβ ligand of aspect 22A, wherein, X¹ is selectedfrom an amino acid comprising a large hydrophobic side chain; X² isselected from an amino acid; X³ is selected from an amino acid; X⁴ isselected from an amino acid; X⁵ is selected from an amino acidcomprising a small hydrophobic side chain; X⁶ is selected from an aminoacid comprising a polar-neutral or an acidic side chain; X⁷ is selectedfrom an amino acid comprising a large hydrophobic side chain; X⁸ isselected from an amino acid comprising a small hydrophobic side chain;X⁹ is selected from an amino acid comprising a polar-neutral or anacidic side chain; X¹⁰ is selected from an amino acid comprising a largehydrophobic side chain; X¹¹ is selected from an amino acid comprising apolar-neutral or an acidic side chain; and X¹² is selected from an aminoacid comprising a large hydrophobic side chain.

Aspect 24A. The IL-2Rβ ligand of any one of aspects 22A to 23A, wherein,X¹ is selected from I, L, M, V, F, W, and Y; X² is selected from anamino acid; X³ is selected from an amino acid; X⁴ is selected from anamino acid; X⁵ is selected from A, G, P, S, and T; X⁶ is selected fromH, N, Q, S, T, Y, D, and E; X⁷ is selected from I, L, M, V, F, W, and Y;X⁸ is selected from A, G, P, S, and T; X⁹ is selected from H, N, Q, S,T, Y, D, and E; X¹⁰ is selected from I, L, M, V, F, W, and Y; X¹¹ isselected from H, N, Q, S, T, Y, D, and E; and X¹² is selected from I, L,M, V, F, W, and Y.

Aspect 25A. The IL-2Rβ ligand of any one of aspects 22A to 23A, wherein,X¹ is selected from I, L, M, V, F, W, and Y; X² is selected from anamino acid; X³ is selected from an amino acid; X⁴ is selected from anamino acid; X⁵ is A; X⁶ is selected from H, N, Q, S, T, Y, D, and E; X⁷is selected from I, L, M, V, F, W, and Y; X⁸ is G; X⁹ is selected fromH, N, Q, S, T, Y, D, and E; X¹⁰ is selected from I, L, M, V, F, W, andY; X¹¹ is selected from H, N, Q, S, T, Y, D, and E; and X¹² is selectedfrom I, L, M, V, F, W, and Y.

Aspect 26A. The IL-2Rβ ligand of aspect 25A, wherein X¹ is selected fromI, L, M, and V.

Aspect 27A. The IL-2Rβ ligand of any one of aspects 25A to 26A, whereinX² is selected from D and E.

Aspect 28A. The IL-2Rβ ligand of any one of aspects 25A to 27A, whereinX⁶ is selected from Q, E, and D.

Aspect 29A. The IL-2Rβ ligand of any one of aspects 25A to 28A, whereinX⁷ is selected from V, L, and I.

Aspect 30A. The IL-2Rβ ligand of any one of aspects 25A to 29A, whereinX⁹ is selected from E, D, and Q.

Aspect 31A. The IL-2Rβ ligand of any one of aspects 25A to 30A, whereinX¹⁰ is selected from L, V, I, and Y.

Aspect 32A. The IL-2Rβ ligand of any one of aspects 25A to 31A, whereinX¹¹ is selected from D and E.

Aspect 33A. The IL-2Rβ ligand of any one of aspects 25A to 32A, whereinX¹² is selected from L, I, and F.

Aspect 34A. The IL-2Rβ ligand of aspect 25A, wherein, X¹ is selectedfrom L, I, F, and V; X² is selected from D and E; X⁶ is selected from Q,E, and D; X⁷ is selected from V, L, and I; X⁹ is selected from E, D, andQ; X¹⁰ is selected from L, V, I, and Y; X¹¹ is selected from D and E;and X¹² is selected from L, I, and F.

Aspect 35A. The IL-2Rβ ligand of aspect 25A, wherein, X¹ is selectedfrom F, I, M, and Y; X² is selected from E, D, and R; X³ is selectedfrom and amino acid; X⁴ is selected from an amino acid; X⁵ is A; X⁶ isselected from A, P, and Q; X⁷ is selected from I and V; X⁸ is G; X⁹ isselected from E and Q; X¹⁰ is selected from I, L, and V; X¹¹ is selectedfrom E, D, and Q; and X¹² is selected from I and L.

Aspect 36A. The IL-2Rβ ligand of aspect 22A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 4to SEQ ID NO: 163:

Aspect 37A. The IL-2Rβ ligand of aspect 36A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 4to SEQ ID NO: 163, wherein the amino acid sequence is terminated withamino acids -G-G- on the N-terminus, on the C-terminus, or on both theN- and C-termini.

Aspect 38A. The IL-2Rβ ligand of any one of aspects 36A to 37A, whereinthe IL-2Rβ ligand comprises an amino acid sequence selected from any oneof SEQ ID NO: 4 to SEQ ID NO: 163, wherein each amino acid independentlycomprises one or more of the following conservative substitutions: aminoacids having a small hydrophobic side chain comprising alanine (A),glycine (G), proline (P), serine (S), or threonine (T); amino acidshaving a hydroxyl-containing side chain comprising serine (S), threonine(T), or tyrosine (Y); amino acids having an acidic side chain comprisingaspartate (D) or glutamate (E); amino acids having a polar-neutral sidechain comprising histidine (H), asparagine (N), glutamine (Q), serine(S), threonine (T), or tyrosine (Y); amino acids having a basic sidechain comprising arginine (R), lysine (K), or histidine (H); amino acidshaving a large hydrophobic side chain comprising isoleucine (I), leucine(L), methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 39A. The IL-2Rβ ligand of any one of aspects 1A to 9A, whereinthe IL-2Rβ ligand comprises the amino acid sequence of Formula (2) (SEQID NO: 164), the amino acid sequence of Formula (2a) (SEQ ID NO: 165),or the amino acid sequence of Formula (2b) (SEQ ID NO: 166):

—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—  (2)

—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—  (2a)

—X¹³—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—X²⁴—  (2b)

-   -   wherein, X¹³ is selected from A, D, E, G, N, Q, R, and V; X¹⁴ is        selected from E, F, I, L, M, and Q; X¹⁵ is selected from D, G,        L, and N; X¹⁶ is selected from L, P, V, and Y; X¹⁷ is selected        from F, G, and M; X¹⁸ is selected from A, D, N, and Q; X¹⁹ is        selected from F, I, L, S, V, W, and Y; X²⁰ is selected from D        and W; X²¹ is selected from P and Y; X²² is selected from A, D,        Q, and S; X²³ is selected from I, L, Q, W, and Y; and X²⁴ is        selected from E, F, I, L, T, V, and W.

Aspect 40A. The IL-2Rβ ligand of aspect 39A, wherein X¹⁶ is V.

Aspect 41A. The IL-2Rβ ligand of any one of aspects 39A to 40A, whereinX¹⁷ is G.

Aspect 42A. The IL-2Rβ ligand of any one of aspects 39A to 41A, whereinX²⁰ is W.

Aspect 43A. The IL-2Rβ ligand of any one of aspects 39A to 42A, whereinX²¹ is P.

Aspect 44A. The IL-2Rβ ligand of aspect 39A, wherein, X¹³ is selectedfrom E, N, and Q; X¹⁴ is selected from I and M; X¹⁵ is selected from D,L, and N; X¹⁶ is V; X¹⁷ is G; X¹⁸ is selected from D and Q; X¹⁹ isselected from V, W, and Y; X²⁰ is W; X²¹ is P; X²² is selected from Dand S; X²³ is selected from L and Q; and X²⁴ is selected from I, L, andV.

Aspect 45A. The IL-2Rβ ligand of aspect 39A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 167to SEQ ID NO: 182.

Aspect 46A. The IL-2Rβ ligand of aspect 45A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 167to SEQ ID NO: 182, wherein the amino acid sequence is terminated withamino acids -G-G- on the N-terminus, on the C-terminus, or on both theN- and C-termini.

Aspect 47A. The IL-2Rβ ligand of any one of aspects 45A to 46A, whereinthe IL-2Rβ ligand comprises an amino acid sequence selected from any oneof SEQ ID NO: 167 to SEQ ID NO: 182, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 48A. The IL-2Rβ ligand of any one of aspects 1A to 9A, whereinthe IL-2Rβ ligand comprises the amino acid sequence of Formula (2) (SEQID NO: 1058), the amino acid sequence of Formula (2a) (SEQ ID NO: 1059),or the amino acid sequence of Formula (2b) (SEQ ID NO: 1060):

—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—  (2)

—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—  (2a)

—X¹³—X¹⁴—C—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—C—X²³—X²⁴—  (2b)

-   -   wherein, X¹³ is selected from an amino acid; X¹⁴ is selected        from an amino acid comprising a large hydrophobic side chain;        X¹⁵ is selected from an amino acid; X¹⁶ is selected from an        amino acid comprising a large hydrophobic side chain; X¹⁷ is        selected from an amino acid comprising a small hydrophobic side        chain; X¹⁸ is selected from an amino acid; X¹⁹ is selected from        an amino acid; X²⁰ is selected from an amino acid comprising a        large hydrophobic side chain; X²¹ is elected from an amino acid        comprising a small hydrophobic side chain; X²² is selected from        an amino acid; X²³ is selected from an amino acid; and X²⁴ is        selected from an amino acid comprising a large hydrophobic side        chain.

Aspect 49A. The IL-2Rβ ligand of aspect 48A, wherein, X³ is selectedfrom an amino acid; X¹⁴ is selected from an amino acid comprising alarge hydrophobic side chain; X¹⁵ is selected from an amino acid; X¹⁶ isselected from an amino acid comprising a large hydrophobic side chain;X¹⁷ is selected from an amino acid comprising a small hydrophobic sidechain; X¹⁸ is selected from an amino acid comprising a polar-neutral oran acidic side chain; X¹⁹ is selected from an amino acid comprisinglarge hydrophobic or neutral side chain; X²⁰ is selected from an aminoacid comprising a large hydrophobic side chain; X²¹ is selected from anamino acid comprising a small hydrophobic side chain; X²² is selectedfrom an amino acid; X²³ is selected from an amino acid; and X²⁴ isselected from an amino acid comprising a large hydrophobic side chain.

Aspect 50A. The IL-2Rβ ligand of any one of aspects 48A to 49A, wherein,X³ is selected from an amino acid; X¹⁴ is selected from I, L, M, V, F,W, and Y; X¹⁵ is selected from D, E, I, L, M, V, F, Y, and W; X¹⁶ isselected from I, L, M, N, V, F, Y, and W; X¹⁷ is selected from A, G, P,S, and T; X¹⁸ is selected from H, N, Q, S, T, Y, D, and E; X¹⁹ isselected from I, L, M, V, F, W, and Y; X²⁰ is selected from I, L, M, N,V, F, Y, and W; X²¹ is selected from A, G, P, S, and T; X²² is selectedfrom an amino acid; X²³ is selected from an amino acid; and X²⁴ isselected from I, L, M, V, F, W, and Y.

Aspect 51A. The IL-2Rβ ligand of aspect 50A, wherein X¹⁴ is selectedfrom I and M.

Aspect 52A. The IL-2Rβ ligand of any one of aspects 50A to 51A, whereinX¹⁶ is V.

Aspect 53A. The IL-2Rβ ligand of any one of aspects 50A to 52A, whereinX¹⁷ is G.

Aspect 54A. The IL-2Rβ ligand of any one of aspects 50A to 53A, whereinX¹⁸ is selected from D and Q.

Aspect 55A. The IL-2Rβ ligand of any one of aspects 50A to 54A, whereinX²⁰ is W.

Aspect 56A. The IL-2Rβ ligand of any one of aspects 50A to 55A, whereinX²¹ is P.

Aspect 57A. The IL-2Rβ ligand of any one of aspects 50A to 56A, whereinX²³ is selected from F, I, L, and V.

Aspect 58A. The IL-2Rβ ligand of aspect 50A, wherein, X¹³ is selectedfrom an amino acid; X¹⁴ is selected from I and M; X¹⁵ is selected froman amino acid; X¹⁶ is V; X¹⁷ is G; X¹⁸ is selected from D and Q; X¹⁹ isselected from I, L, M, V, F, W, and Y; X²⁰ is W; X²¹ is P; X²² isselected from an amino acid; X²³ is selected from an amino acid; and X²⁴is selected from F, I, L, and V.

Aspect 59A. The IL-2Rβ ligand of any one of aspects 1A to 9A, whereinthe IL-2Rβ ligand comprises the amino acid sequence of Formula (3) (SEQID NO: 183) or the amino acid sequence of Formula (3a) (SEQ ID NO: 184):

—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—  (3)

—X²⁵—C—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—C—X³⁶—  (3a)

-   -   wherein, X²⁵ is selected from an amino acid; X²⁶ is selected        from an amino acid; X²⁷ is selected from I and V; X²⁸ is G; X²⁹        is selected from D, E, and N; X³⁰ is selected from F, L, and Y;        X³¹ is selected from F, I, and V; X³² is selected from D and Q;        X³³ is selected from an amino acid; X³⁴ is selected from an        amino acid; X³⁵ is selected from an amino acid; and X³⁶ is        selected from an amino acid.

Aspect 60A. The IL-2Rβ ligand of aspect 59A, wherein, X²⁵ is selectedfrom L, S, T, and Y; X²⁶ is selected from H and Q; X²⁷ is selected fromI and V; X²⁸ is G; X²⁹ is selected from D, E, and N; X³⁰ is selectedfrom F, L, and Y; X³¹ is selected from F, I, and V; X³² is selected fromD and Q; X³³ is selected from D, L, and W; X³⁴ is selected from G, L,and T; X³⁵ is selected from D, I, and S; and X³⁶ is selected from A andM.

Aspect 61A. The IL-2Rβ ligand of any one of aspects 1A to 9A, whereinthe IL-2Rβ ligand comprises the amino acid sequence of Formula (3) (SEQID NO: 1061) or the amino acid sequence of Formula (3a) (SEQ ID NO:1062):

—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—  (3)

—X²⁵—C—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—C—X³⁶—  (3a)

-   -   wherein, X²⁵ is selected from an amino acid; X²⁶ is selected        from an amino acid; X²⁷ is selected from an amino acid        comprising a large hydrophobic side chain; X²⁸ is selected from        an amino acid comprising a small hydrophobic side chain; X²⁹ is        selected from an amino acid comprising an acidic side chain or a        polar neutral side chain; X³⁰ is selected from an amino acid;        X³¹ is selected from an amino acid; X³² is selected from an        amino acid comprising a polar-neutral side chain or an acidic        side chain; X³³ is selected from an amino acid; X³⁴ is selected        from an amino acid; X³⁵ is selected from an amino acid; and X³⁶        is selected from an amino acid.

Aspect 62A. The IL-2Rβ ligand of aspect 61A, wherein X²⁵ is selectedfrom an amino acid; X²⁶ is selected from an amino acid; X²⁷ is selectedfrom an amino acid comprising a large hydrophobic side chain; X²⁸ isselected from an amino acid comprising a small hydrophobic side chain;X²⁹ is selected from an amino acid comprising an acidic side chain or apolar neutral side chain; X³⁰ is selected from an amino acid comprisinga large hydrophobic side chain; X³¹ is selected from an amino acidcomprising a large hydrophobic side chain; X³² is selected from an aminoacid comprising a polar-neutral side chain or an acidic side chain; andX³³ is selected from an amino acid; X³⁴ is selected from an amino acid;X³⁵ is selected from an amino acid; and X³⁶ is selected from an aminoacid.

Aspect 63A. The IL-2Rβ ligand of any one of aspects 1A to 9A, whereinthe IL-2Rβ ligand comprises the amino acid sequence of Formula (3) (SEQID NO: 1063) or the amino acid sequence of Formula (3a) (SEQ ID NO:1064):

—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—  (3)

—X²⁵—C—X²⁶—X²⁷—X²⁸—X²⁹—X³⁰—X³¹—X³²—X³³—X³⁴—X³⁵—C—X³⁶—  (3a)

-   -   wherein, X²⁵ is selected from an amino acid; X²⁶ is selected        from an amino acid; X²⁷ is selected from I, L, M, V, F, Y, and        W; X²⁸ is selected from A, G, P, S, and T; X²⁹ is selected from        D, E, H, N, Q, S, T, and Y; X³⁰ is selected from I, L, M, V, F,        Y, and W; X³¹ is selected from I, L, M, V, F, Y, and W; X³² is        selected from D, E, H, N, Q, T, and Y; X³³ is selected from an        amino acid; X³⁴ is selected from an amino acid; X³⁵ is selected        from an amino acid; and X³⁶ is selected from an amino acid.

Aspect 64A. The IL-2Rβ ligand of aspect 63A, wherein X²⁷ is selectedfrom V and I.

Aspect 65A. The IL-2Rβ ligand of any one of aspects 63A to 64A, whereinX²⁸ is G.

Aspect 66A. The IL-2Rβ ligand of any one of aspects 63A to 65A, whereinX²⁹ is selected from D and E.

Aspect 67A. The IL-2Rβ ligand of any one of aspects 63A to 66A, whereinX³⁰ is selected from V, L, F, and Y.

Aspect 68A. The IL-2Rβ ligand of any one of aspects 63A to 67A, whereinX³¹ is selected from I, V, and F.

Aspect 69A. The IL-2Rβ ligand of any one of aspects 63A to 68A, whereinX³² is selected from Q and D.

Aspect 70A. The IL-2Rβ ligand of aspect 63A, wherein, X²⁵ is selectedfrom an amino acid; X²⁶ is selected from an amino acid; X²⁷ is selectedfrom V and I; X²⁸ is G; X²⁹ is selected from D and E; X³⁰ is selectedfrom V, L, F, and Y; X³¹ is selected from I, V, and F; X³² is selectedfrom Q and D; X³³ is selected from an amino acid; X³⁴ is selected froman amino acid; X³⁵ is selected from an amino acid; and X³⁶ is selectedfrom an amino acid.

Aspect 71A. The IL-2Rβ ligand of aspect 63A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 185to SEQ ID NO: 193:

Aspect 72A. The IL-2Rβ ligand of aspect 71A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 185to SEQ ID NO: 193, wherein the amino acid sequence is terminated withamino acids -G-G- on the N-terminus, on the C-terminus, or on both theN- and C-termini.

Aspect 73A. The IL-2Rβ ligand of any one of aspects 71A to 72A, whereinthe IL-2Rβ ligand comprises an amino acid sequence selected from any oneof SEQ ID NO: 185 to SEQ ID NO: 193, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); and amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 74A. The IL-2Rβ ligand of any one of aspects 1A to 9A, whereinthe IL-2Rβ ligand comprises the amino acid sequence of Formula (13) (SEQID NO: 1028):

—X²⁰¹—X²⁰²—X²⁰³—X²⁰⁴—X²⁰⁵—X⁰⁶²—X²⁰⁷—X²⁰⁸—X²⁰⁹—X²¹⁰—X²¹¹—X²¹²—  (13)

-   -   wherein, X²⁰¹ is selected from an amino acid; X²⁰² is selected        from an amino acid; X²⁰³ is selected from an amino acid        comprising an acidic side chain; X²⁰⁴ is selected from an amino        acid comprising a large hydrophobic side chain; X²⁰⁵ is selected        from an amino acid comprising a small hydrophobic side chain;        X²⁰⁶ is selected from an amino acid comprising an acidic side        chain; X²⁰⁷ is selected from an amino acid comprising a large        hydrophobic side chain; X²⁰⁸ is selected from an amino acid;        X²⁰⁹ is selected from an amino acid comprising an acidic side        chain; X²¹⁰ is selected from an amino acid; X²¹¹ is selected        from an amino acid; and X²¹² is selected from an amino acid        comprising a large hydrophobic side chain.

Aspect 75A. The IL-2Rβ ligand of aspect 74A, wherein, X²⁰¹ is selectedfrom an amino acid; X²⁰² is selected from an amino acid; X²⁰³ isselected from D and E; X²⁰⁴ is selected from I, L, M, V, F, Y, and W;X²⁰⁵ is selected from A, G, P, S, and T; X²⁰⁵ is selected from D and E;X²⁰⁷ is selected from I, L, M, V, F, Y, and W; X²⁰⁸ is selected from anamino acid; X²⁰⁹ is selected from D and E; X²¹⁰ is selected from anamino acid; X²¹¹ is selected from an amino acid; and X²¹² is selectedfrom I, L, M, V, F, Y, and W.

Aspect 76A. The IL-2Rβ ligand of aspect 74A, wherein, X²⁰¹ is selectedfrom C, F, L, S, and W; X²⁰² is selected from C, D, F, G, L, M, Q, S, V,W, and Y; X²⁰³ is selected from A, C, D, E, L, M, N, S, W, and Y; X²⁰⁴is selected from A, D, I, M, V, and W; X²⁰⁵ is selected from D, E, G,and I; X²⁰⁶ is selected from C, D, G, H, L, Q, S, and T; X²⁰⁷ isselected from C, D, I, L, V, W, and Y; X²⁰⁸ is selected from C, D, L, V,and W; X²⁰⁹ is selected from C, D, G, I, M, N, P, Q, and W; X²¹⁰ isselected from D, F, L, M, P, S, T, and Y; X²¹¹ is selected from C, F, L,V, and W; and X²¹² is selected from L, N, S, T, and V.

Aspect 77A. The IL-2Rβ ligand of aspect 76A, wherein X²⁰¹ is selectedfrom C, F, L, S, and W.

Aspect 78A. The IL-2Rβ ligand of any one of aspects 76A to 77A, whereinX²⁰² is selected from C, D, F, G, L, M, Q, S, V, W, and Y.

Aspect 79A. The IL-2Rβ ligand of any one of aspects 76A to 78A, whereinX²⁰³ is selected from D and E.

Aspect 80A. The IL-2Rβ ligand of any one of aspects 76A to 79A, whereinX²⁰⁴ is V.

Aspect 81A. The IL-2Rβ ligand of any one of aspects 76A to 80A, whereinX²⁰⁵ is G.

Aspect 82A. The IL-2Rβ ligand of any one of aspects 76A to 81A, whereinX²⁰⁶ is D.

Aspect 83A. The IL-2Rβ ligand of any one of aspects 76A to 82A, whereinX²⁰⁷ is selected from I, W, and Y.

Aspect 84A. The IL-2Rβ ligand of any one of aspects 76A to 83A, whereinX²⁰⁸ is selected from C, D, L, V, and W.

Aspect 85A. The IL-2Rβ ligand of any one of aspects 76A to 84A, whereinX²⁰⁹ is D.

Aspect 86A. The IL-2Rβ ligand of any one of aspects 76A to 85A, whereinX²¹⁰ is selected from D, F, L, M, P, S, T, and Y.

Aspect 87A. The IL-2Rβ ligand of any one of aspects 76A to 86A, whereinX²¹¹ is selected from C, F, L, V, and W.

Aspect 88A. The IL-2Rβ ligand of any one of aspects 76A to 87A, whereinX²¹² is selected from L and V.

Aspect 89A. The IL-2Rβ ligand of aspect 76A, wherein, X²⁰¹ is selectedfrom an amino acid; X²⁰² is selected from an amino acid; X²⁰³ isselected from D and E; X²⁰⁴ is V; X²⁰⁵ is G; X²⁰⁶ is D; X²⁰⁷ is selectedfrom I, Y, and W; X²⁰⁸ is selected from an amino acid; X²⁰⁹ is D; X²¹⁰is selected from an amino acid; X²¹¹ is selected from an amino acid; andX²¹² is selected from I, L, M, V, F, Y, and W.

Aspect 90A. The IL-2Rβ ligand of aspect 76A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO:1028 to SEQ ID NO: 1042 and SEQ ID NO: 1084.

Aspect 91A. The IL-2Rβ ligand of aspect 90A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO:1028 to SEQ ID NO: 1042 and SEQ ID NO: 1084, wherein the amino acidsequence is terminated with amino acids -G-G- on the N-terminus, on theC-terminus, or on both the N- and C-termini.

Aspect 92A. The IL-2Rβ ligand of any one of aspects 90A to 91A, whereinthe IL-2Rβ ligand comprises an amino acid sequence selected from any oneof SEQ ID NO: 1028 to SEQ ID NO: 1042 and SEQ ID NO: 1084, wherein eachamino acid independently comprises one or more of the followingconservative substitutions: amino acids having a small hydrophobic sidechain comprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); and amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 93A. The IL-2Rβ ligand of any one of aspects 1A to 9A, whereinthe IL-2Rβ ligand comprises an amino acid sequence selected from any oneof SEQ ID NO: 1044 to SEQ ID NO: 1050.

Aspect 94A. The IL-2Rβ ligand of aspect 93A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO:1044 to SEQ ID NO: 1050, wherein the amino acid sequence is terminatedwith amino acids -G-G- on the N-terminus, on the C-terminus, or on boththe N- and C-termini.

Aspect 95A. The IL-2Rβ ligand of any one of aspects 93A to 94A, whereinthe IL-2Rβ ligand comprises an amino acid sequence selected from any oneof SEQ ID NO: 1044 to SEQ ID NO: 1050, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); and amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 96A. The IL-2Rβ ligand of any one of aspects 1A to 9A, whereinthe IL-2Rβ ligand comprises the amino acid sequence of Formula (10) (SEQID NO: 578):

—X¹⁹¹—X¹⁹²—X¹⁹³—X¹⁹⁴—X¹⁹⁵—C—X¹⁹⁶—X¹⁹⁷—X¹⁹⁸—X¹⁹⁹—X²⁰⁰—X²⁰¹—X²⁰²—X²⁰³—X²⁰⁴—X²⁰⁵—X²⁰⁶—X²⁰⁷—X²⁰⁸—  (10)

-   -   wherein, X¹⁹¹ is selected from an amino acid comprising a large        hydrophobic side chain or an aromatic side chain; X¹⁹² is        selected from an amino acid; X¹⁹³ is selected from an amino acid        comprising a large hydrophobic side chain or an aromatic side        chain; X¹⁹⁴ is selected from an amino acid comprising a large        hydrophobic side chain or a basic side chain; X¹⁹⁵ is selected        from an amino acid comprising an acidic side chain or a small        hydrophobic side chain; X¹⁹⁶ is selected from an amino acid        comprising a large hydrophobic side chain or a basic side chain;        X¹⁹⁷ is selected from an amino acid comprising a large        hydrophobic side chain; X¹⁹⁸ is selected from an amino acid        comprising a small hydrophobic side chain; X¹⁹⁹ is selected from        an amino acid comprising a polar/neutral side chain or a basic        side chain; X²⁰⁰ is selected from an amino acid comprising a        large hydrophobic side chain; X²⁰¹ is selected from an amino        acid comprising a small hydrophobic side chain; X²⁰² is selected        from an amino acid comprising an acidic side chain or a        polar/neutral side chain; X²⁰³ is selected from an amino acid        comprising a large hydrophobic side chain; X²⁰⁴ is selected from        an amino acid comprising an acidic side chain; X²⁰⁵ is selected        from an amino acid comprising a large hydrophobic side chain;        X¹⁰⁶ is selected from an amino acid comprising an acidic side        chain or an aromatic side chain; X²⁰⁷ is selected from an amino        acid comprising an amino acid; and X²⁰⁸ is selected from an        amino acid comprising an acidic side chain.

Aspect 97A. The IL-2Rβ ligand of aspect 96A, wherein, X¹⁹¹ is selectedfrom F, H, I, L, M, V, W, and Y; X¹⁹² is selected from an amino acid;X¹⁹³ is selected from F, H, I, L, M, V, W, and Y; X¹⁹⁴ is selected fromF, I, L, M, V, W, Y, H, K, and R; X¹⁹⁵ is selected from D, E, A, G, P,S, and T; X¹⁹⁶ is selected from F, I, L, M, V, W, Y, H, K, and R; X¹⁹⁷is selected from F, I, L, M, V, W, and Y; X¹⁹⁸ is selected from A, G, P,S, and T; X¹⁹⁹ is selected from H, N, Q, S, T, Y, H, K, and R; X²⁰⁰ isselected from F, I, L, M, V, W, and Y; X²⁰¹ is selected from A, G, P, S,and T; X²⁰² is selected from D, E, H, N, Q, S, T, and Y; X²⁰³ isselected from F, I, L, M, V, W, and Y; X²⁰⁴ is selected from D and E;X²⁰⁵ is selected from F, I, L, M, V, W, and Y; X²⁰⁶ is selected from D,E, F, H, I, L, M, V, W, and Y; X²⁰⁷ is selected from an amino acid; andX²⁰⁸ is selected from D and E.

Aspect 98A. The IL-2Rβ ligand of aspect 97A, wherein X¹⁹¹ is selectedfrom F, H, W, and Y.

Aspect 99A. The IL-2Rβ ligand of any one of aspects 97A to 98A, whereinX¹⁹¹ is W.

Aspect 100A. The IL-2Rβ ligand of any one of aspects 97A to 99A, whereinX¹⁹² is selected from an amino acid.

Aspect 101A. The IL-2Rβ ligand of any one of aspects 97A to 100A,wherein X¹⁹³ is selected from F, H, W, and Y.

Aspect 102A. The IL-2Rβ ligand of any one of aspects 97A to 100A,wherein X¹⁹³ is selected from F, W, and Y.

Aspect 103A. The IL-2Rβ ligand of any one of aspects 97A to 102A,wherein X¹⁹⁴ is selected from H, L, and Y.

Aspect 104A. The IL-2Rβ ligand of any one of aspects 97A to 102A,wherein X¹⁹⁴ is L.

Aspect 105A. The IL-2Rβ ligand of any one of aspects 97A to 102A,wherein X¹⁹⁴ is Y.

Aspect 106A. The IL-2Rβ ligand of any one of aspects 97A to 105A,wherein X¹⁹⁵ is selected from D and P.

Aspect 107A. The IL-2Rβ ligand of any one of aspects 97A to 105A,wherein X¹⁹⁵ is D.

Aspect 108A. The IL-2Rβ ligand of any one of aspects 97A to 105A,wherein X¹⁹⁵ is P.

Aspect 109A. The IL-2Rβ ligand of any one of aspects 97A to 108A,wherein X¹⁹⁶ is selected from H and W.

Aspect 110A. The IL-2Rβ ligand of any one of aspects 97A to 108A,wherein X¹⁹⁶ is H.

Aspect 111A. The IL-2Rβ ligand of any one of aspects 97A to 108A,wherein X¹⁹⁶ is W.

Aspect 112A. The IL-2Rβ ligand of any one of aspects 97A to 111A,wherein X¹⁹⁷ is M.

Aspect 113A. The IL-2Rβ ligand of any one of aspects 97A to 112A,wherein X¹⁹⁸ is A.

Aspect 114A. The IL-2Rβ ligand of any one of aspects 97AA to 113,wherein X¹⁹⁹ is selected from H, K, R, and Q.

Aspect 115A. The IL-2Rβ ligand of any one of aspects 97A to 113A,wherein X¹⁹⁹ is Q.

Aspect 116A. The IL-2Rβ ligand of any one of aspects 97A to 113A,wherein X¹⁹⁹ is selected from H, K, and R.

Aspect 117A. The IL-2Rβ ligand of any one of aspects 97A to 116A,wherein X²⁰⁰ is selected from L and V.

Aspect 118A. The IL-2Rβ ligand of any one of aspects 97A to 116A,wherein X²⁰⁰ is L.

Aspect 119A. The IL-2Rβ ligand of any one of aspects 97A to 118A,wherein X²⁰¹ is G.

Aspect 120A. The IL-2Rβ ligand of any one of aspects 97A to 119A,wherein X²⁰² is selected from D, E, and Q.

Aspect 121A. The IL-2Rβ ligand of any one of aspects 97A to 119A,wherein X²⁰² is E.

Aspect 122A. The IL-2Rβ ligand of any one of aspects 97A to 121A,wherein X²⁰³ is L.

Aspect 123A. The IL-2Rβ ligand of any one of aspects 97A to 122A,wherein X²⁰⁴ is selected from D and E.

Aspect 124A. The IL-2Rβ ligand of any one of aspects 97A to 122A,wherein X²⁰⁴ is D.

Aspect 125A. The IL-2Rβ ligand of any one of aspects 97A to 124A,wherein X²⁰⁵ is L.

Aspect 126A. The IL-2Rβ ligand of any one of aspects 97A to 125A,wherein X²⁰⁵ is selected from D and E.

Aspect 127A. The IL-2Rβ ligand of any one of aspects 97A to 126A,wherein X²⁰⁷ is selected from an amino acid.

Aspect 128A. The IL-2Rβ ligand of any one of aspects 97A to 127A,wherein X²⁰⁸ is selected from D and E.

Aspect 129A. The IL-2Rβ ligand of aspect 97A, wherein, X¹⁹¹ is selectedfrom F, H, W, and Y; X¹⁹² is selected from an amino acid; X¹⁹³ isselected from F, H, W, and Y; X¹⁹⁴ is selected from H, L, and Y; X¹⁹⁵ isselected from D and P; X¹⁹⁶ is selected from H, R, and W; X¹⁹⁷ is M;X¹⁹⁸ is A; X¹⁹⁹ is selected from H, K, R, and Q; X²⁰⁰ is selected from Land V; X²⁰¹ is G; X²⁰² is selected from D, E, and Q; X²⁰³ is L; X²⁰⁴ isselected from D and E; X²⁰⁵ is L; X²⁰⁶ is selected from D, E, H, F, W,and Y; X²⁰⁷ is selected from an amino acid; and X²⁰⁸ is selected from Dand E.

Aspect 130A. The IL-2Rβ ligand of aspect 96A, wherein, X¹⁹¹ is selectedfrom F, H, W, and Y; X¹⁹² is selected from an amino acid; X¹⁹³ is Y;X¹⁹⁴ is selected from H, L, and Y; X¹⁹⁵ is D; X¹⁹⁶ is W; X¹⁹⁷ is M; X¹⁹⁸is A; X¹⁹⁹ is Q; X²⁰⁰ is selected from L and V; X²⁰¹ is G; X²⁰² isselected from D, E, and Q; X²⁰³ is L; X²⁰⁴ is selected from D and E;X²⁰⁵ is L; X²⁰⁶ is selected from D and E; X²⁰⁷ is selected from an aminoacid; and X²⁰⁸ is selected from D and E.

Aspect 131A. The IL-2Rβ ligand of aspect 96A, wherein, X¹⁹¹ is selectedfrom F, H, W, and Y; X¹⁹² is selected from an amino acid; X¹⁹³ is Y;X¹⁹⁴ is selected from H, L, and Y; X¹⁹⁵ is D; X¹⁹⁶ is H; X¹⁹⁷ is M; X¹⁹⁸is A; X¹⁹⁹ is Q; X²⁰⁰ is selected from L and V; X²⁰¹ is G; X²⁰² isselected from D, E, and Q; X²⁰³ is L; X²⁰⁴ is selected from D and E;X²⁰⁵ is L; X²⁰⁶ is selected from D and E; X²⁰⁷ is selected from an aminoacid; and X²⁰⁸ is selected from D and E.

Aspect 132A. The IL-2Rβ ligand of aspect 96A, wherein, X¹⁹¹ is selectedfrom F, H, W, and Y; X¹⁹² is selected from an amino acid; X¹⁹³ is Y;X¹⁹⁴ is selected from H, L, and Y; X¹⁹⁵ is D; X¹⁹⁶ is R; X¹⁹⁷ is M; X¹⁹⁸is A; X¹⁹⁹ is Q; X²⁰⁰ is selected from L and V; X²⁰¹ is G; X²⁰² isselected from D, E, and Q; X²⁰³ is L; X²⁰⁴ is selected from D and E;X²⁰⁵ is L; X²⁰⁶ is selected from D and E; X²⁰⁷ is selected from an aminoacid; and X²⁰⁸ is selected from D and E.

Aspect 133A. The IL-2Rβ ligand of aspect 96A, wherein, X¹⁹¹ is selectedfrom F, H, W, and Y; X¹⁹² is selected from an amino acid; X¹⁹³ is Y;X¹⁹⁴ is selected from H, L, and Y; X¹⁹⁵ is P; X¹⁹⁶ is W; X¹⁹⁷ is M; X¹⁹⁸is A; X¹⁹⁹ is Q; X²⁰⁰ is selected from L and V; X²⁰¹ is G; X²⁰² isselected from D, E, and Q; X²⁰³ is L; X²⁰⁴ is selected from D and E;X²⁰⁵ is L; X²⁰⁶ is selected from D and E; X²⁰⁷ is selected from an aminoacid; and X²⁰⁸ is selected from D and E.

Aspect 134A. The IL-2Rβ ligand of aspect 96A, wherein, X¹⁹¹ is selectedfrom F, H, W, and Y; X¹⁹² is selected from an amino acid; X¹⁹³ is Y;X¹⁹⁴ is selected from H, L, and Y; X¹⁹⁵ is D; X¹⁹⁶ is W; X¹⁹⁷ is M; X¹⁹⁸is A; X¹⁹⁹ is selected from H, K, and R; X²⁰⁰ is selected from L and V;X²⁰¹ is G; X²⁰² is selected from D, E, and Q; X²⁰³ is L; X²⁰⁴ isselected from D and E; X²⁰⁵ is L; X²⁰⁶ is selected from D and E; X²⁰⁷ isselected from an amino acid; and X²⁰⁸ is selected from D and E.

Aspect 135A. The IL-2Rβ ligand of aspect 96A, wherein, X¹⁹¹ is selectedfrom F, H, W, and Y; X¹⁹² is selected from an amino acid; X¹⁹³ is Y;X¹⁹⁴ is selected from H, L, and Y; X¹⁹⁵ is D; X¹⁹⁶ is W; X¹⁹⁷ is M; X¹⁹⁸is A; X¹⁹⁹ is Q; X²⁰⁰ is selected from L and V; X²⁰¹ is G; X²⁰² isselected from D, E, and Q; X²⁰³ is L; X²⁰⁴ is selected from D and E;X²⁰⁵ is L; X²⁰⁶ is selected from F, H, W, and Y; X²⁰⁷ is selected froman amino acid; and X²⁰⁸ is selected from D and E.

Aspect 136A. The IL-2Rβ ligand of aspect 96A, wherein, X¹⁹¹ is selectedfrom A, D, E, F, G, H, I, K, L, N, M, P, Q, R, S, T, V, W, and Y; X¹⁹²is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,and Y; X¹⁹³ is selected from A, C, D, F, G, H, I, L, M, N P, R, S, T, V,W, and Y; X¹⁹⁴ is selected from F, H, I, K, L, N, P, Q, R, S, T, V, W,and Y; X¹⁹⁵ is selected from A, D, E, F, G, H, K, L, M, N, P, Q, S, W,and Y; X¹⁹⁶ is selected from A, E, F, G, H, Q, R, S, W, and Y; X¹⁹⁷ isselected from A, D, E, F, I, K, L, M, N, Q, R, S, T, V, W, and Y; X¹⁹⁸is A; X¹⁹⁹ is selected from A, D, H, K, L, N, P, Q, R, S, and Y; X²⁰⁰ isselected from I, L, M, P, and V; X²⁰¹ is selected from G, H, and W; X²⁰²is selected from D, E, and Q; X²⁰³ is L; X²⁰⁴ is selected from A, D, E,H, I, L, T, V, and Y; X²⁰⁵ is selected from F, I, L, M, V, W, and Y;X²⁰⁶ is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V,W, and Y; X²⁰⁷ is selected from A, C, D, E, F, G, H, I, L, M, N, P, Q,R, S, T, V, W, and Y; and X²⁰⁸ is selected from A, D, E, F, G, H, K, L,M, N, P, Q, R, S, T, V, W, and Y.

Aspect 137A. The IL-2Rβ ligand of aspect 136A, wherein, X¹⁹¹ is selectedfrom F, H, W, and Y; X¹⁹² is selected from A, D, E, F, G, H, I, K, L, M,N, P, Q, R, S, T, V, W, and Y; X¹⁹³ is selected from F, H, W, and Y;X¹⁹⁴ is selected from F, H, I, L, V W, and Y; X¹⁹⁵ is selected from D,E, and P; X¹⁹⁶ is selected from F, H, R, S, W, and Y; X¹⁹⁷ is selectedfrom F, I, L, M, and V; X¹⁹⁸ is A; X¹⁹⁹ is selected from H, K, N, Q, andR; X²⁰⁰ is selected from I, L, and V; X²⁰¹ is G; X²⁰² is selected fromD, E, and Q; X²⁰³ is selected from F, I, L, M, V, and Y; X²⁰⁴ isselected from D and E; X²⁰⁵ is L; X²⁰⁶ is selected from D, E, N, and Q;X²⁰⁷ is selected from A, D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, W,and Y; and X²⁰⁸ is selected from D and E.

Aspect 138A. The IL-2Rβ ligand of aspect 136A, wherein, X¹⁹¹ is W; X¹⁹²is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,and Y; X¹⁹³ is selected from F, H, W, and Y; X¹⁹⁸ is Y; X¹⁹⁵ is selectedfrom D, E, and P; X¹⁹⁶ is selected from H, R, and W; X¹⁹⁷ is selectedfrom I and M; X¹⁹⁸ is A; X¹⁹⁹ is selected from K, Q, and R; X²⁰⁰ isselected from I, L, and V; X²⁰¹ is G; X²⁰² is E; X²⁰³ is L; X²⁰⁴ is D;X²⁰⁵ is L; X²⁰⁶ is selected from D and E; X²⁰⁷ is selected from A, D, E,F, G, H, I, L, M, N, P, Q, R, S, T, V, W, and Y; and X²⁰⁸ U is selectedfrom D and E.

Aspect 139A. The IL-2Rβ ligand of aspect 136A, wherein, X¹⁹¹ is selectedfrom A, D, E, F, G, H, I, K, L, N, M, P, Q, R, S, T, V, W, and Y; X¹⁹²is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W,and Y; X¹⁹³ is selected from F, H, W, and Y; X¹⁹⁴ is selected from F, H,L, W, and Y; X¹⁹⁵ is selected from D, E, and P; X¹⁹⁶ is selected from F,H, R, S, W, and Y; X¹⁹⁷ is selected from F, I, L, M, and V; X¹⁹⁸ is A;X¹⁹⁹ is selected from H, K, Q, N, and R; X²⁰⁰ is selected from I, L, andV; X²⁰¹ is G; X²⁰² is selected from D, E, and Q; X²⁰³ is L; X²⁰⁴ isselected from D and E; X²⁰⁵ is selected from F, I, L, M, V, and W; X²⁰⁶is selected from D, E, F, I, L, M, V, W, and Y; X²⁰⁷ is selected from A,D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, W, and Y; and X²⁰⁸ isselected from D and E.

Aspect 140A. The IL-2Rβ ligand of aspect 139A, wherein X¹⁹¹ is selectedfrom A, D, E, F, G, H, I, K, L, N, M, P, Q, R, S, T, V, W, and Y.

Aspect 141A. The IL-2Rβ ligand of any one of aspects 139A to 140A,wherein X¹⁹¹ is selected from A, G, P, S, and T.

Aspect 142A. The IL-2Rβ ligand of any one of aspects 139A to 140A,wherein X¹⁹¹ is selected from F, H, I, L, M, V, W, and Y.

Aspect 143A. The IL-2Rβ ligand of any one of aspects 139A to 140A,wherein X¹⁹¹ is selected from F, H, W, and Y.

Aspect 144A. The IL-2Rβ ligand of any one of aspects 139A to 143A,wherein X¹⁹² is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R,S, T, V, W, and Y.

Aspect 145A. The IL-2Rβ ligand of any one of aspects 139A to 143A,wherein X¹⁹² is selected from A, G, P, S, and T.

Aspect 146A. The IL-2Rβ ligand of any one of aspects 139A to 143A,wherein X¹⁹² is selected from F, H, I, L, M, V, W, and Y.

Aspect 147A. The IL-2Rβ ligand of any one of aspects 139A to 146A,wherein X¹⁹³ is selected from F, H, W, and Y.

Aspect 148A. The IL-2Rβ ligand of any one of aspects 139A to 146A,wherein X¹⁹³ is W.

Aspect 149A. The IL-2Rβ ligand of any one of aspects 139A to 148A,wherein X¹⁹⁴ is selected from F, H, L, W, and Y.

Aspect 150A. The IL-2Rβ ligand of any one of aspects 139A to 148A,wherein X¹⁹⁴ is selected from H, L, and Y.

Aspect 151A. The IL-2Rβ ligand of any one of aspects 139A to 148A,wherein X¹⁹⁴ is Y.

Aspect 152A. The IL-2Rβ ligand of any one of aspects 139A to 151A,wherein X¹⁹⁵ is selected from D, E, and P.

Aspect 153A. The IL-2Rβ ligand of any one of aspects 139A to 151A,wherein X¹⁹⁵ is D.

Aspect 154A. The IL-2Rβ ligand of any one of aspects 139A to 151A,wherein X¹⁹⁵ is P.

Aspect 155A. The IL-2Rβ ligand of any one of aspects 139A to 154A,wherein X¹⁹⁶ is selected from F, H, R, S, W, and Y.

Aspect 156A. The IL-2Rβ ligand of any one of aspects 139A to 154A,wherein X¹⁹⁶ is selected from H, and W.

Aspect 157A. The IL-2Rβ ligand of any one of aspects 139A to 154A,wherein X¹⁹⁶ is W.

Aspect 158A. The IL-2Rβ ligand of any one of aspects 139A to 157A,wherein X¹⁹⁷ is selected from F, I, L, M, and V.

Aspect 159A. The IL-2Rβ ligand of any one of aspects 139A to 157A,wherein X¹⁹⁷ is selected from I and M.

Aspect 160A. The IL-2Rβ ligand of any one of aspects 139A to 157A,wherein X¹⁹⁷ is M.

Aspect 161A. The IL-2Rβ ligand of any one of aspects 139A to 160A,wherein X¹⁹⁸ is A.

Aspect 162A. The IL-2Rβ ligand of any one of aspects 139A to 161A,wherein X¹⁹⁹ is selected from H, K, Q, N, and R.

Aspect 163A. The IL-2Rβ ligand of any one of aspects 139A to 161A,wherein X¹⁹⁹ is selected from H, K, and R.

Aspect 164A. The IL-2Rβ ligand of any one of aspects 139A to 161A,wherein X¹⁹⁹ is Q.

Aspect 165A. The IL-2Rβ ligand of any one of aspects 139A to 164A,wherein X²⁰⁰ is selected from I, L, and V.

Aspect 166A. The IL-2Rβ ligand of any one of aspects 139A to 164A,wherein X²⁰⁰ is selected from L and V.

Aspect 167A. The IL-2Rβ ligand of any one of aspects 139A to 166A,wherein X²⁰¹ is G.

Aspect 168A. The IL-2Rβ ligand of any one of aspects 139A to 167A,wherein X²⁰² is selected from D, E, and Q.

Aspect 169A. The IL-2Rβ ligand of any one of aspects 139A to 167A,wherein X²⁰² is E.

Aspect 170A. The IL-2Rβ ligand of any one of aspects 139A to 169A,wherein X²⁰³ is L.

Aspect 171A. The IL-2Rβ ligand of any one of aspects 139A to 170A,wherein X²⁰⁴ is selected from D and E.

Aspect 172A. The IL-2Rβ ligand of any one of aspects 139A to 170A,wherein X²⁰⁴ is D.

Aspect 173A. The IL-2Rβ ligand of any one of aspects 139A to 171A,wherein X²⁰⁵ is selected from F, I, L, M, V, and W.

Aspect 174A. The IL-2Rβ ligand of any one of aspects 139A to 171A,wherein X²⁰⁵ is L.

Aspect 175A. The IL-2Rβ ligand of any one of aspects 139A to 174A,wherein X²⁰⁶ is selected from D and E.

Aspect 176A. The IL-2Rβ ligand of any one of aspects 139A to 174A,wherein X²⁰⁶ is D.

Aspect 177A. The IL-2Rβ ligand of any one of aspects 139A to 174A,wherein X²⁰⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 178A. The IL-2Rβ ligand of any one of aspects 139A to 177A,wherein X²⁰⁷ is selected from A, D, E, F, G, H, I, L, M, N, P, Q, R, S,T, V, W, and Y.

Aspect 179A. The IL-2Rβ ligand of any one of aspects 139A to 177A,wherein X²⁰⁷ is selected from A, G, P, S, and T.

Aspect 180A. The IL-2Rβ ligand of any one of aspects 139A to 177A,wherein X²⁰⁷ is selected from F, I, L, M, V, W, and Y.

Aspect 181A. The IL-2Rβ ligand of any one of aspects 139A to 180A,wherein X²⁰⁸ is selected from D and E.

Aspect 182A. The IL-2Rβ ligand of aspect 139A, wherein, X¹⁹¹ is selectedfrom F, I, L, M, V, W, and Y; X¹⁹² is selected from A, D, E, F, G, H, I,K, L, M, N, P, Q, R, S, T, V, W, and Y; X¹⁹³ is selected from F, H, W,and Y; X¹⁹⁴ is selected from H, L, and Y; X¹⁹⁵ is selected from D and P;X¹⁹⁶ is selected from H, R, and W; X¹⁹⁷ is selected from I and M; X¹⁹⁸is A; X¹⁹⁹ is selected from H, K, Q, and R; X²⁰⁰ is selected from L andV; X²⁰¹ is G; X²⁰² is selected from D, E, and Q; X²⁰³ is L; X²⁰⁴ isselected from D and E; X²⁰⁵ is L; X²⁰⁶ is selected from D, E, F, I, L,M, V, W, and Y; X²⁰⁷ is selected from A, D, E, F, G, H, I, L, M, N, P,Q, R, S, T, V, W, and Y; and X²⁰⁸ is selected from D and E.

Aspect 183A. The IL-2Rβ ligand of aspect 139A, wherein, X¹⁹¹ is selectedfrom F, I, L, M, V, W, and Y; X¹⁹² is selected from A, D, E, F, G, H, I,K, L, M, N, P, Q, R, S, T, V, W, and Y; X¹⁹³ is W; X¹⁹⁴ is Y; X¹⁹⁵ isselected from D and P; X¹⁹⁶ is W; X¹⁹⁷ is M; X¹⁹⁸ is A; X¹⁹⁹ is Q; X¹⁹⁹is selected from H, K, and R; X²⁰⁰ is selected from L and V; X²⁰¹ is G;X²⁰² is E; X²⁰³ is L; X²⁰⁴ is selected from D and E; X²⁰⁵ is L; X²⁰⁶ isD; X²⁰⁷ is selected from A, D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V,W, and Y; and X²⁰⁸ is selected from D and E.

Aspect 184A. The IL-2Rβ ligand of aspect 139A, wherein, X¹⁹¹ is selectedfrom F, I, L, M, V, W, and Y; X¹⁹³ is W; X¹⁹⁵ is Y; X¹⁹⁵ is selectedfrom D and P; X¹⁹⁶ is selected from H, R, and W; X¹⁹⁷ is M; X¹⁹⁸ is A;X¹⁹⁹ is selected from H, K, Q, and R; X²⁰⁰ is selected from L and V;X²⁰¹ is G; X²⁰² is E; X²⁰³ is L; X²⁰⁴ is D; X²⁰⁵ is L; X²⁰⁶ is D; X²⁰⁷is selected from A, D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, W, andY; and X²⁰⁸ is selected from D and E.

Aspect 185A. The IL-2Rβ ligand of aspect 97A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 579to SEQ ID NO: 808.

Aspect 186A. The IL-2Rβ ligand of aspect 185A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 579to SEQ ID NO: 808, wherein the amino acid sequence is terminated withamino acids -G-G- on the N-terminus, on the C-terminus, or on both theN- and C-termini.

Aspect 187A. The IL-2Rβ ligand of any one of aspects 185A to 186A,wherein the IL-2Rβ ligand comprises an amino acid sequence selected fromany one of SEQ ID NO: 579 to SEQ ID NO: 808, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); and amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 188A. The IL-20 ligand of any one of aspects 1A to 9A, whereinthe IL-20 ligand comprises the amino acid sequence of Formula (11) (SEQID NO: 809):

—X²¹¹—X²¹²—X²¹³—X²¹⁴—C—X²¹⁵—X²¹⁶—X²¹⁷—X²¹⁸—X²¹⁹—X²²⁰—X²²¹—X²²²—X²²³—X²²⁴—X²²⁵—  (11)

-   -   wherein, X²¹¹ is selected from an amino acid; X²¹² is selected        from an amino acid comprising an aromatic side chain; X²¹³ is        selected from an amino acid comprising a large hydrophobic side        chain or an aromatic side chain; X²¹⁴ is P; X²¹⁵ is selected        from an amino acid comprising an aromatic side chain; X²¹⁶ is        selected from an amino acid comprising a large hydrophobic side        chain; X²¹⁷ is A; X²¹⁸ is selected from an amino acid comprising        a basic side chain or a polar/neutral side chain; X²¹⁹ is        selected from an amino acid comprising a large hydrophobic side        chain; X²²⁰ is G; X²²¹ is selected from an amino acid comprising        an acidic side chain or a polar/neutral side chain; X²²² is L;        X²²³ is D; X²²⁴ is selected from an amino acid comprising a        large hydrophobic side chain; and X²²⁵ is selected from an amino        acid comprising an acidic side chain.

Aspect 189A. The IL-2Rβ ligand of aspect 188A, wherein, X²¹¹ is selectedfrom an amino acid; X²¹² is selected from F, H, W, and Y; X²¹³ isselected from F, H, I, L, M, V, W, and Y; X²¹⁴ is P; X²¹⁵ is selectedfrom F, H, W, and Y; X²¹⁶ is selected from F, I, L, M, V, W, and Y; X²¹⁷is A; X²¹⁸ is selected from K, R, H, N, Q, S, T, and Y; X²¹⁹ is selectedfrom F, I, L, M, V, W, and Y; X²²⁰ is G; X²²¹ is selected from D, E, H,N, Q, S, T, and Y; X²²² is L; X²²³ is D; X²²⁴ is selected from F, I, L,M, V, W, and Y; and X²²⁵ is selected from D and E.

Aspect 190A. The IL-2Rβ ligand of aspect 189A, wherein X²¹¹ is selectedfrom an amino acid.

Aspect 191A. The IL-2Rβ ligand of any one of aspects 189A to 190A,wherein X²¹¹ is selected from H, K, and R.

Aspect 192A. The IL-2Rβ ligand of any one of aspects 189A to 190A,wherein X²¹² is selected from H and R.

Aspect 193A. The IL-2Rβ ligand of any one of aspects 189A to 192A,wherein X²¹² is selected from F, H, W, and Y.

Aspect 194A. The IL-2Rβ ligand of any one of aspects 189A to 192A,wherein X²¹² is W.

Aspect 195A. The IL-2Rβ ligand of any one of aspects 189A to 194A,wherein X²¹³ is selected from F, H, I, L, M, V, W, and Y.

Aspect 196A. The IL-2Rβ ligand of any one of aspects 189A to 194A,wherein X²¹³ is L.

Aspect 197A. The IL-2Rβ ligand of any one of aspects 189A to 194A,wherein X²¹³ is Y.

Aspect 198A. The IL-2Rβ ligand of any one of aspects 189A to 197A,wherein X²¹⁴ is P.

Aspect 199A. The IL-2Rβ ligand of any one of aspects 189A to 198A,wherein X²¹⁵ is selected from F, H, W, and Y.

Aspect 200A. The IL-2Rβ ligand of any one of aspects 189A to 198A,wherein X²¹⁵ is W.

Aspect 201A. The IL-2Rβ ligand of any one of aspects 189A to 200A,wherein X²¹⁶ is selected from F, I, L, M, V, W, and Y.

Aspect 202A. The IL-2Rβ ligand of any one of aspects 189A to 200A,wherein X²¹⁶ is M.

Aspect 203A. The IL-2Rβ ligand of any one of aspects 189A to 202A,wherein X²¹⁷ is A.

Aspect 204A. The IL-2Rβ ligand of any one of aspects 189A to 203A,wherein X²¹⁸ is selected from K, R, H, N, Q, S, T, and Y.

Aspect 205A. The IL-2Rβ ligand of any one of aspects 189A to 203A,wherein X²¹⁸ is selected from K and R.

Aspect 206A. The IL-2Rβ ligand of any one of aspects 189A to 203A,wherein X²¹⁸ is Q.

Aspect 207A. The IL-2Rβ ligand of any one of aspects 189A to 206A,wherein X²¹⁹ is selected from F, I, L, M, V, W, and Y.

Aspect 208A. The IL-2Rβ ligand of any one of aspects 189A to 206A,wherein X²¹⁹ is L.

Aspect 209A. The IL-2Rβ ligand of any one of aspects 189A to 208A,wherein X²²⁰ is G.

Aspect 210A. The IL-2Rβ ligand of any one of aspects 189A to 209A,wherein X²²¹ is selected from D, E, H, N, Q, S, T, and Y.

Aspect 211A. The IL-2Rβ ligand of any one of aspects 189A to 209A,wherein X²²¹ is E.

Aspect 212A. The IL-2Rβ ligand of any one of aspects 189A to 211A,wherein X²²² is L.

Aspect 213A. The IL-2Rβ ligand of any one of aspects 189A to 212A,wherein X²²³ is D.

Aspect 214A. The IL-2Rβ ligand of any one of aspects 189A to 213A,wherein X²²⁴ is selected from F, I, L, M, V, W, and Y.

Aspect 215A. The IL-2Rβ ligand of any one of aspects 189A to 213A,wherein X²²⁴ is L.

Aspect 216A. The IL-2Rβ ligand of any one of aspects 189A to 215A,wherein X²²⁵ is selected from D and E.

Aspect 217A. The IL-2Rβ ligand of aspect 188A, wherein, X²¹¹ is selectedfrom H, K, and R; X²¹² is W; X²¹³ is Y; X²¹⁴ is P; X²¹⁵ is W; X²¹⁶ is M;X²¹⁷ is A; X²¹⁸ is selected N and Q; X²¹⁹ is selected from L and V; X²²⁰is G; X²²¹ is selected from E, D, and Q; X²²² is L; X²²³ is D; X²²⁴ isselected from L and M; and X²²⁵ is selected from D and E.

Aspect 218A. The IL-2Rβ ligand of aspect 188A, wherein, X²¹¹ is selectedfrom A, D, E, G, H, L, M, N, Q, R, S, T, and V; X²¹² is selected from C,F, W, and Y; X²¹³ is selected from F, H, K, L, N, Q, R, S, W, and Y;X²¹⁴ is P; X²¹⁵ is selected from W and Y; X²¹⁶ is selected from F, I, K,L, M, R, S, T, and V; X²¹⁷ is A; X²¹⁸ is selected from D, E, G, H, K, L,N, Q, R, S, and Y; X²¹⁹ is selected from L, P, and V; X²²⁰ is selectedfrom G, H, and W; X²²¹ is selected from D, E, and Q; X²²² is selectedfrom L and M; X²²³ is D; X²²⁴ is selected from L, M, Q, and V; and X²²⁵is selected from A, D, E, F, G, H, L, N, Q, T, and V.

Aspect 219A. The IL-2Rβ ligand of aspect 218A, wherein, X²¹¹ is selectedfrom H an R; X²¹² is selected from F and W; X²¹³ is selected from F, L,W, and Y; X²¹⁴ is P; X²¹⁵ is selected from W and Y; X²¹⁶ is selectedfrom F, I, L, M, and V; X²¹⁷ is A; X²¹⁸ is selected D, E, H, K, N, Q,and R; X²¹⁹ is selected from L and V; X²²⁰ is G; X²²¹ is selected fromD, E, and Q; X²²² is selected from L and M; X²²³ is D; X²²⁴ is selectedL, M, and V; and X²⁵⁵ is selected from D and E.

Aspect 220A. The IL-2Rβ ligand of aspect 218A, wherein, X²¹¹ is selectedfrom H and R; X²¹² is W; X²¹³ is Y; X²¹⁴ is P; X²¹⁵ is W; X²¹⁶ is M;X²¹⁷ is A; X²¹⁸ is Q; X²¹⁹ is L; X²²⁰ is G; X²²¹ is Q; X²²² is L; X²²³is D; X²²⁴ is L; and X²²⁵ is selected from D and E.

Aspect 221A. The IL-2Rβ ligand of aspect 218A, wherein, X²¹¹ is selectedfrom H and R; X²¹² is W; X²¹³ is L; X²¹⁴ is P; X²¹⁵ is W; X²¹⁶ is M;X²¹⁷ is A; X²¹⁸ is Q; X²¹⁹ is L; X²²⁰ is G; X²²¹ is Q; X²²² is L; X²²³is D; X²²⁴ is L; and X²²⁵ is selected from D and E.

Aspect 222A. The IL-2Rβ ligand of aspect 218A, wherein, X²¹¹ is selectedfrom H and R; X²¹² is W; X²¹³ is Y; X²¹⁴ is P; X²¹⁵ is W; X²¹⁶ is M;X²¹⁷ is A; X²¹⁸ is selected from K and R; X²¹⁹ is L; X²²⁰ is G; X²²¹ isQ; X²²² is L; X²²³ is D; X²²⁴ is L; and X²²⁵ is selected from D and E.

Aspect 223A. The IL-2Rβ ligand of aspect 188A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 810to SEQ ID NO: 903.

Aspect 224A. The IL-2Rβ ligand of aspect 223A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 810to SEQ ID NO: 903, wherein the amino acid sequence is terminated withamino acids -G-G- on the N-terminus, on the C-terminus, or on both theN- and C-termini.

Aspect 225A. The IL-2Rβ ligand of any one of aspects 223A to 224A,wherein the IL-2Rβ ligand comprises an amino acid sequence selected fromany one of SEQ ID NO: 810 to SEQ ID NO: 903, wherein each amino acidindependently comprises one or more of the following conservativesubstitutions: amino acids having a small hydrophobic side chaincomprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); and amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 226A. The IL-2Rβ ligand of aspect 1A, wherein the IL-2Rβ ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 1to SEQ ID NO: 193, SEQ ID NO: 578 to SEQ ID NO: 903, and SEQ ID NO: 1028to SEQ ID NO: 1043, and SEQ ID NOS 1052-1064 and 1084.

Aspect 227A. The IL-2Rβ ligand of any one of aspects 1A to 226A, whereinthe IL-2Rβ ligand does not comprise the amino acid sequence of SEQ IDNO: 268 and to SEQ ID NO: 374.

Aspect 228A. A compound comprising at least one IL-2Rβ ligand of any oneof aspects 1A to 227A.

Aspect 229A. The compound of aspect 228A, wherein the compound furthercomprises at least one IL-2Rγc ligand of any one of SEQ ID NO: 194 toSEQ ID NO: 267 and SEQ ID NO: 904 to SEQ ID NO: 1027 and SEQ ID NOS1065-1083.

Aspect 230A. The compound of any one of aspects 228A to 229A, whereinthe compound comprises a least one IL-2Rγc ligand.

Aspect 231A. The compound of any one of aspects 228A to 230A, whereinthe compound comprises an IL-2Rγc ligand, a linker, and an IL-2Rβligand.

Aspect 232A. The compound of aspect 231A, wherein the linker comprises apeptide linker.

Aspect 233A. The compound of aspect 231A, wherein the C-terminus of theIL-2Rγc ligand is covalently bound to the linker and the C-terminus ofthe IL-2Rβ ligand is bound to the linker.

Aspect 234A. The compound of aspect 231A, wherein the N-terminus of theIL-2Rγc ligand is covalently bound to the linker and the C-terminus ofthe IL-2Rβ ligand is bound to the linker.

Aspect 235A. The compound of aspect 231A, wherein the C-terminus of theIL-2Rγc ligand is covalently bound to the linker and the N-terminus ofthe IL-2Rβ ligand is bound to the linker.

Aspect 236A. The compound of aspect 231A, wherein the N-terminus of theIL-2Rγc ligand is covalently bound to the linker and the N-terminus ofthe IL-2Rβ ligand is bound to the linker.

Aspect 237A. The compound of any one of aspects 228A to 236A, whereinthe compound is selected from a peptide, a conjugate, a fusion protein,and a single chain peptide.

Aspect 238A. The compound of any one of aspects 228A to 237A, whereinthe compound comprises at least one moiety configured to modify aproperty of the conjugate.

Aspect 239A. The compound of aspect 238A, wherein the property isselected from aqueous solubility, polarity, lipophilicity,pharmacokinetic profile, targeting, bioavailability, pH-dependentbinding, bioactivity, pharmacodynamics, cellular activity, metabolism,efficacy, caging (reversible incapacitation), and a combination of anyof the foregoing.

Aspect 240A. The compound of any one of aspects 238A to 239A, whereinthe at least one moiety comprises a small molecule, a polymer, apeptide, or an antibody.

Aspect 241A. The compound of any one of aspects 228A to 240A, comprisinga pharmacokinetic moiety.

Aspect 242A. The compound of aspect 241A, wherein the pharmacokineticmoiety comprises a polyethylene glycol.

Aspect 243A. The compound of any one of aspects 228A to 242A, comprisinga tumor-targeting moiety.

Aspect 244A. The compound of aspect 243A, wherein the tumor-targetingmoiety comprises a tumor-specific antibody, a tumor-specific antibodyfragment, a tumor-specific protein, or a tumor-specific peptide.

Aspect 245A. The compound of any one of aspects 228A to 244A, comprisingan immune cell-targeting moiety.

Aspect 246A. The compound of any one of aspects 228A to 245A, whereinthe compound is an IL-2R agonist.

Aspect 247A. The compound of any one of aspects 228A to 246A, whereinthe compound is an IL-2R antagonist.

Aspect 248A. The compound of any one of aspects 228A to 247A, whereinthe compound comprises a fusion protein, wherein the IL-2Rβ ligand isbound to a fusion partner.

Aspect 249A. The compound of aspect 248A, wherein the fusion proteinpartner comprises an IgG molecule, an IgG FAb fragment, or an Fcfragment,

Aspect 250A. The compound of aspect 248A, wherein the protein fusionpartner comprises an IL-2, a variant of IL-2, a mutant of IL-2, or anIL-2R agonist.

Aspect 251A. The compound of any one of aspects 228A to 250A, whereinthe compound comprises a label.

Aspect 252A. The compound of aspect 251A, wherein the label is selectedfrom a radioisotope, a fluorophore, or a combination thereof.

Aspect 253A. The compound of any one of aspects 228A to 252A, whereinthe compound comprises a cage to protect peripheral tissues fromtoxicity of IL-2R activation.

Aspect 254A. The compound of any one of aspects 228A to 253A, whereinthe compound comprises a moiety configured to target IL-2R-directedimmuno-stimulation of the effector immune cells in the tumor.

Aspect 255A. The compound of any one of aspects 228A to 254A, whereinthe compound comprises a cleavable moiety.

Aspect 256A. The compound of any one of aspects 228A to 240A, whereinthe compound comprises a moiety that is toxic to cells expressing highlevels of the IL-2Rβ subunit.

Aspect 257A. The compound of aspect 256A, wherein the cells expressinghigh levels of the IL-2Rβ subunit comprise cancer cells.

Aspect 258A. The compound of any one of aspects 228A to 257A, whereinthe compound comprises an imaging agent, a diagnostic agent, a targetingagent, a therapeutic agent, or a combination of any of the foregoing.

Aspect 259A. The compound of any one of aspects 228A to 258A, whereinthe compound comprises a moiety configured to target IL-2R-directedimmuno-stimulation of effector immune cells in a tumor.

Aspect 260A. A pharmaceutical composition comprising; an IL-2Rβ ligandof any one of aspects 1A to 227A; a compound of any one of aspects 228Ato 259A; or a combination thereof.

Aspect 261A. The pharmaceutical composition of aspect 260A, furthercomprising: an IL-2Rγc ligand of any one of SEQ ID NO: 194 to SEQ ID NO:267 and SEQ ID NO: 904 to SEQ ID NO: 1027 and SEQ ID NOS 1065-1083; acompound comprising an IL-2Rγc ligand of any one of SEQ ID NO: 194 toSEQ ID NO: 267 and SEQ ID NO: 904 to SEQ ID NO: 1027 and SEQ ID NOS1065-1083; or a combination thereof.

Aspect 262A. A method of treating cancer in a patient, comprisingadministering to a patient in need of such treatment, a therapeuticallyeffective amount of the pharmaceutical composition of aspect 260A.

Aspect 263A. The method of aspect 262A, wherein the cancer comprises asolid tumor.

Aspect 264A. A method of treating an autoimmune disease in a patient,comprising administering to a patient in need of such treatment, atherapeutically effective amount of the pharmaceutical composition ofany one of aspects 260A to 261A.

Aspect 265A. A method of screening compounds for IL-2Rβ activity,comprising: contacting a cell with, the IL-2Rβ ligand of any one ofaspects 1A to 227A; the compound of any one of aspects 228A to 259A; ora combination of any of the foregoing; wherein the cell expresses theIL-2Rβ subunit; and contacting the cell with a test compound; anddetermining the activity of the test compound.

Aspect 266A. A method of activating the human IL-2 receptor, comprisingcontacting a cell expressing the human IL-2 receptor in vivo with acompound comprising: the IL-2Rβ ligand of any one of aspects 1A to 227Aand an IL-2Rγc ligand of any one of SEQ ID NO: 194 to SEQ ID NO: 267 andSEQ ID NO: 904 to SEQ ID NO: 1027 and SEQ ID NOS 1065-1083, or acompound of any one of aspects 228A to 259A.

Aspect 267A. A method of activating the human IL-2 receptor in apatient, comprising contacting a cell expressing the human IL-2 receptorin vivo with a compound comprising: the IL-2Rβ ligand of any one ofaspects 1A to 227A and an IL-2Rγc ligand of any one of SEQ ID NO: 194 toSEQ ID NO: 267 and SEQ ID NO: 904 to SEQ ID NO: 1027 and SEQ ID NOS1065-1083, or a compound of any one of aspects 228A to 259A.

Aspect 268A. A method of treating a disease in a patient, wherein theIL-2 receptor signaling pathway is associated with the etiology of thedisease, comprising administering to a patient in need of such treatmenta therapeutically effective amount of a compound comprising the IL-2Rβligand of any one of aspects 1A to 227A, or a compound of any one ofaspects 228A to 259A.

Aspect 269A. A method of treating a disease in a patient, whereinactivation of the IL-2 receptor is effective in treating the disease,comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound comprising the IL-2Rβligand of any one of aspects 1A to 227A, or a compound of any one ofaspects 228A to 259A.

Aspect 270A. A method of treating a disease in a patient, whereininhibition of the IL-2 receptor is effective in treating the disease,comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound comprising the IL-2Rβligand of any one of aspects 1A to 227A, or a compound of any one ofaspects 228A to 259A.

Aspect 271A. A method of treating a disease in a patient, wherein cellsexpressing the IL-2Rβ subunit are associated with the etiology of thedisease, comprising administering to a patient in need of such treatmenta therapeutically effective amount of a compound comprising the IL-2Rβligand of any one of aspects 1A to 227A, or a compound of any one ofaspects 228A to 259A.

Aspect 272A. A method of treating a disease in a patient, whereinactivation of IL-2R is effective in treating the disease, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound comprising the IL-2Rβ ligand of any oneof aspects 1A to 227A, or a compound of any one of aspects 228A to 259A.

Aspect 273A. A method of treating a disease in a patient, whereininhibiting IL-2R is effective in treating the disease, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound comprising the IL-2Rβ ligand of any oneof aspects 1A to 227A, or a compound of any one of aspects 228A to 259A.

Aspect 274A. A method of treating a disease in a patient, whereinreducing the sensitivity of Treg cells to IL-2 is effective in treatingthe disease, comprising administering to a patient in need of suchtreatment a therapeutically effective amount of a compound comprisingthe IL-2Rβ ligand of any one of aspects 1A to 227A, or a compound of anyone of aspects 228A to 259A.

Aspect 275A. A method of imaging cells expressing the IL-2Rβ subunitcomprising administering to a patient an effective amount of a compoundcomprising the IL-2Rβ ligand of any one of aspects 1A to 227A, or acompound of any one of aspects 228A to 259A.

Aspect 276A. A method of diagnosing a disease in a patient wherein thedisease is associated with cells expressing the IL-2Rβ subunitcomprising: administering to a patient an effective amount of a compoundcomprising the IL-2Rβ ligand of any one of aspects 1A to 227A, or acompound of any one of aspects 228A to 259A; and determining abiodistribution of the compound comprising the IL-2Rβ ligand of any oneof aspects 1A to 227A, or a compound of any one of aspects 228A to 259A.

Aspect 277A. A method of treating a disease in a patient, comprising:contacting a biological sample from a patient with an IL-2Rβ ligand ofany one of aspects 1A to 227A or a compound comprising an IL-2Rβ ligandof any one of aspects 1A to 227A; determining at least one propertyassociated with binding of the IL-2Rβ ligand to cells of the biologicalsample; and administering to the patient having the disease a compoundcomprising an IL-2Rβ ligand of any one of aspects 1A to 227A based onthe at least one determined property.

Aspect 278A. The method of aspect 277A, wherein the at least oneproperty comprises: an expression level of the IL-2Rβ subunit in cellsof the biological sample; a characterization of cells of the biologicalsample expressing the IL-2Rβ subunit; and/or a binding affinity (IC₅₀)of cells of the biological sample expressing the IL-2Rβ subunit.

Aspect 279A. A method of targeting a compound to cells expressing theIL-2Rβ subunit comprising administering to a patient an effective amountof a compound comprising: the IL-2Rβ ligand of any one of aspects 1A to227A; and a targeting moiety.

Aspect 280A. A method of delivering a cytotoxic compound to cellsexpressing the IL-2Rγc subunit comprising administering to a patient aneffective amount of a compound comprising: an IL-2Rβ ligand of any oneof aspects 1A to 227A; and cytotoxic moiety.

Aspect 281A. A binding site of the IL-2Rβ subunit, wherein the group ofIL-2Rβ ligands having amino acid sequences of SEQ ID NOS: 1-163,164-182, 578-808, 1028-1043, 1052-1060 and 1084, competitively bind tothe binding site with each of the other IL-2Rβ ligands within the group;an IL-2Rβ ligand having amino acid sequence of SEQ ID NO: 1044 does notcompete for binding to the binding site with the group of IL-2Rβligands; and IL-2 does not compete for binding to the binding site withthe group of IL-2Rβ ligands.

Aspect 282A. The binding site of aspect 281A, wherein each IL-2Rβ ligandof the group of IL-2Rβ ligands has a binding affinity (IC₅₀) to theIL-2Rβ subunit of less than 100 μM.

Aspect 283A. The binding site of any one of aspects 281A to 282A,wherein each IL-2Rβ ligand of the group of IL-2Rβ ligands has a bindingaffinity (IC₅₀) to the IL-2Rγc subunit of greater than 100 μM.

Aspect 284A. The binding site of any one of aspects 281A to 283A,wherein an IL-2Rγc ligand having the amino acid sequence of SEQ ID NO:224 does not compete for binding to the binding site with the group ofIL-2Rβ ligands.

Aspect 285A. The binding site of any one of aspects 281A to 284A,wherein the group of IL-2Rβ ligands comprises IL-2Rβ ligands having theamino acid sequence of SEQ ID NOS: 58, 83, 142, 169, 170, and 1042.

Aspect 1B. An IL-2Rγc ligand, wherein the IL-2Rγc ligand exhibits abinding affinity (IC₅₀) to the human IL-2Rγc subunit of less than 100pM.

Aspect 2B. The IL-2Rγc ligand of aspect 1B, wherein the IL-2Rγc ligandcomprises from 5 to 30 amino acids.

Aspect 3B. The IL-2Rγc ligand of any one of aspects 1B to 2B, whereinthe IL-2Rγc ligand exhibits a binding affinity (IC₅₀) to the humanIL-2Rγc subunit in a range from 1 pM to 100 μM.

Aspect 4B. The IL-2Rγc ligand of any one of aspects 1B to 2B, whereinthe IL-2Rγc ligand exhibits a binding affinity (IC₅₀) to the humanIL-2Rγc subunit in a range from 0.1 μM to 50 μM.

Aspect 5B. The IL-2Rγc ligand of any one of aspects 1B to 2B, whereinthe IL-2Rγc ligand exhibits a binding affinity (IC₅₀) to the humanIL-2Rγc subunit of less than 100 μM.

Aspect 6B. The IL-2Rγc ligand of any one of aspects 1B to 2B, whereinthe IL-2Rγc ligand exhibits a binding affinity (IC₅₀) to each of thehuman IL-2Rβ subunit and to the human IL-2Rγc subunit of less than 100μM.

Aspect 7B. The IL-2Rγc ligand of any one of aspects 1B to 2B, whereinthe IL-2Rγc ligand exhibits a binding affinity (IC₅₀) to the humanIL-2Rα subunit of greater than 100 μM.

Aspect 8B. The IL-2Rγc ligand of any one of aspects 1B to 2B, whereinthe IL-2Rγc ligand exhibits a binding affinity (IC₅₀) to the humanIL-2Rγc subunit that is at least 10 times greater than the bindingaffinity (IC₅₀) of the IL-2Rγc ligand to the human IL-2Rα subunit.

Aspect 9B. The IL-2Rγc ligand of any one of aspects 1B to 8B, whereinthe IL-2Rγc ligand comprises the amino acid sequence of Formula (4) (SEQID NO: 1069) or the amino acid sequence of Formula (4a) (SEQ ID NO:1070):

—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—  (4)

—X⁵¹—X⁵²—C—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—C—X⁶¹—X⁶²—  (4a)

-   -   wherein, X⁵¹ is selected from G, I, K, L, Q, R, T, Y, and V; X⁵²        is selected from A, D, E, H, I, L, M, R, S, T, V, and W; X⁵³ is        selected from D, E, F, N, Q, S, and T; X⁵⁴ is selected from A,        D, E, G, I, M, N, Q, R, S, and T; X⁵⁵ is selected from D, E, F,        S, T, W, and Y; X⁵⁶ is selected from D, E, F, G, L, M, N, Q, and        Y; X⁵⁷ is selected from E, G, N, S, and Q; X⁵⁸ is selected from        I, K, M, P, T, and V; X⁵⁹ is selected from I, L, M, S, T, and V;        X⁶⁰ is selected from F, I, and L; X⁶¹ is selected from F, T, and        W; and X⁶² is selected from, E, F, G, I, K, L, M, N, P, Q, S, T,        V, W, and Y.

Aspect 10B. The IL-2Rγc ligand of aspect 9B, wherein X⁵¹ is selectedfrom I, L, and V.

Aspect 11B. The IL-2Rγc ligand of any one of aspects 9B to 10B, whereinX⁵² is selected from S and T.

Aspect 12B. The IL-2Rγc ligand of any one of aspects 9B to 11B, whereinX⁵³ is selected from D, E, N, and Q.

Aspect 13B. The IL-2Rγc ligand of any one of aspects 9B to 12B, whereinX⁵⁴ is selected from D, E, N, and Q.

Aspect 14B. The IL-2Rγc ligand of any one of aspects 9B to 13B, whereinX⁵⁵ is selected from F, W, and Y.

Aspect 15B. The IL-2Rγc ligand of any one of aspects 9B to 14B, whereinX⁵⁶ is selected from D, E, N, and Q.

Aspect 16B. The IL-2Rγc ligand of any one of aspects 9B to 15B, whereinX⁵⁷ is G.

Aspect 17B. The IL-2Rγc ligand of any one of aspects 9B to 16B, whereinX⁵⁸ is selected from I and V.

Aspect 18B. The IL-2Rγc ligand of any one of aspects 9B to 17B, whereinX⁵⁹ is selected from I, L, M, and V.

Aspect 19B. The IL-2Rγc ligand of any one of aspects 9B to 18B, whereinX⁶⁰ is selected from F, I, and L.

Aspect 20B. The IL-2Rγc ligand of any one of aspects 9B to 19B, whereinX⁶¹ is W.

Aspect 21B. The IL-2Rγc ligand of any one of aspects 9B to 20B, whereinX⁶² is selected from N and Q.

Aspect 22B. The IL-2Rγc ligand of aspect 9B, wherein, X⁵¹ is selectedfrom I, L, and V; X⁵² is selected from S and T; X⁵³ is selected from D,E, N, and Q; X⁵⁴ is selected from D and N; X⁵⁵ is selected from F, W,and Y; X⁵⁶ is selected from D, E, N, and Q; X⁵⁷ is G; X⁵⁸ is selectedfrom I and V; X⁵⁹ is selected from I, L, M, and V; X⁶⁰ is selected fromF, I, and L; X⁶¹ is W; and X⁶² is selected from N and Q.

Aspect 23B. The IL-2Rγc ligand of aspect 9B, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 196to SEQ ID NO: 210 and SEQ ID NO: 904 to SEQ ID NO: 913.

Aspect 24B. The IL-2Rγc ligand of aspect 23B, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 196to SEQ ID NO: 210 and SEQ ID NO: 904 to SEQ ID NO: 913, wherein theamino acid sequence is terminated with amino acids -G-G- on theN-terminus, on the C-terminus, or on both the N- and C-termini.

Aspect 25B. The IL-2Rγc ligand of aspect 23B, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 196to SEQ ID NO: 210 and SEQ ID NO: 904 to SEQ ID NO: 913, wherein eachamino acid independently comprises one or more of the followingconservative substitutions: amino acids having a small hydrophobic sidechain comprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 26B. The IL-2Rγc ligand of any one of aspects 1B to 8B, whereinthe IL-2Rγc ligand comprises the amino acid sequence of Formula (4) (SEQID NO: 1065) or the amino acid sequence of Formula (4a) (SEQ ID NO:1066):

—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—  (4)

—X⁵¹—X⁵²—C—X⁵³—X⁵⁴—X⁵⁵—X⁵⁶—X⁵⁷—X⁵⁸—X⁵⁹—X⁶⁰—C—X⁶¹—X⁶²—  (4a)

-   -   wherein, X⁵¹ is selected from an amino acid; X⁵² is selected        from an amino acid; X⁵³ is selected from an amino acid        comprising a polar-neutral side chain or an acidic side chain;        X⁵⁴ is selected from an amino acid comprising a polar-neutral        side chain or an acidic side chain; X⁵⁵ is selected from an        amino acid; X⁵⁶ is selected from an amino acid; X⁵⁷ is selected        from an amino acid comprising a small hydrophobic side chain;        X⁵⁸ is selected from an amino acid comprising a large        hydrophobic side chain; X⁵⁹ is selected from an amino acid        comprising a large hydrophobic side chain; X⁶⁰ is selected from        an amino acid comprising a large hydrophobic side chain; X⁶¹ is        selected from an amino acid comprising a large hydrophobic side        chain; and X⁶² is selected from an amino acid.

Aspect 27B. The IL-2Rγc ligand of aspect 26B, wherein, X⁵¹ is selectedfrom an amino acid comprising a large hydrophobic side chain and a basicside chain; X⁵² is selected from an amino acid comprising ahydroxyl-containing side chain and a large hydrophobic side chain; X⁵³is selected from an amino acid comprising a polar-neutral side chain oran acidic side chain; X⁵⁴ is selected from an amino acid comprising apolar-neutral side chain or an acidic side chain; X⁵⁵ is selected froman amino acid comprising a large hydrophobic side chain; X⁵⁶ is selectedfrom an amino acid comprising a polar-neutral side chain or an acidicside chain; X⁵⁷ is selected from an amino acid comprising a smallhydrophobic side chain; X⁵⁸ is selected from an amino acid comprising alarge hydrophobic side chain; X⁵⁹ is selected from an amino acidcomprising a large hydrophobic side chain; X⁶⁰ is selected from an aminoacid comprising a large hydrophobic side chain; X⁶¹ is selected from anamino acid comprising a large hydrophobic side chain; and X⁶² isselected from an amino acid comprising a polar-neutral side chain.

Aspect 28B. The IL-2Rγc ligand of any one of aspects 26B to 27B,wherein, X⁵¹ is selected from R, K, H, F, I, L, M, V, Y, and W; X⁵² isselected from S, T, F, I, L, M, V, Y, and W; X⁵³ is selected from D, E,H, N, Q, S, T, and Y; X⁵⁴ is selected from D, E, H, N, Q, S, T, and Y;X⁵⁵ is selected from F, I, L, M, V, Y, and W; X⁵⁶ is selected from D, E,H, N, Q, S, T, and Y; X⁵⁷ is selected from A, G, P, S, and T; X⁵⁸ a isselected from F, I, L, M, V, Y, and W; X⁵⁹ is selected from F, I, L, M,V, Y, and W; X⁶⁰ is selected from F, I, L, M, V, Y, and W; X⁶¹ isselected from F, I, L, M, V, Y, and W; and X⁶² is selected from H, N, Q,S, T, and Y.

Aspect 29B. The IL-2Rγc ligand of aspect 28B, wherein X⁵¹ is selectedfrom I, L, and V.

Aspect 30B. The IL-2Rγc ligand of any one of aspects 28B to 29B, whereinX⁵² is selected from S and T.

Aspect 31B. The IL-2Rγc ligand of any one of aspects 28B to 30B, whereinX⁵³ is selected from D, E, and Q.

Aspect 32B. The IL-2Rγc ligand of any one of aspects 28B to 31B, whereinX⁵⁴ is selected from D, E, and N.

Aspect 33B. The IL-2Rγc ligand of any one of aspects 28B to 32B, whereinX⁵⁵ is selected from F, Y, and W.

Aspect 34B. The IL-2Rγc ligand of any one of aspects 28B to 33B, whereinX⁵⁶ is selected from D, E, N, and Q.

Aspect 35B. The IL-2Rγc ligand of any one of aspects 28B to 34B, whereinX⁵⁷ is G.

Aspect 36B. The IL-2Rγc ligand of any one of aspects 28B to 35B, whereinX⁵⁸ is selected from I and V.

Aspect 37B. The IL-2Rγc ligand of any one of aspects 28B to 36B, whereinX⁵⁹ is selected from I, L, M, and V.

Aspect 38B. The IL-2Rγc ligand of any one of aspects 28B to 37B, whereinX⁶⁰ is selected from F, I, and L.

Aspect 39B. The IL-2Rγc ligand of any one of aspects 28B to 38B, whereinX⁶¹ is W.

Aspect 40B. The IL-2Rγc ligand of any one of aspects 28B to 39B, whereinX⁶² is selected from N and Q.

Aspect 41B. The IL-2Rγc ligand of aspect 28B, wherein, X⁵¹ is selectedfrom I, L, and V; X⁵² is selected from S and T; X⁵³ is selected from D,E, and Q; X⁵⁴ is selected from D, E, and N; X⁵⁵ is selected from F, Y,and W; X⁵⁶ is selected from D, E, N, and Q; X⁵⁷ is G; X⁵⁸ is selectedfrom I and V; X⁵⁹ is selected from I, L, M, and V; X⁶⁰ is selected fromF, I, and L; X⁶¹ is W; and X⁶² is selected from N and Q.

Aspect 42B. The IL-2Rγc ligand of aspect 1B, wherein the IL-2Rγc ligandcomprises the amino acid sequence of Formula (5) (SEQ ID NO: 211) orFormula (5a) (SEQ ID NO: 212):

—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—  (5)

—X⁷¹—X⁷²—C—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—C—X⁸¹—X⁸²—  (5a)

-   -   wherein, X⁷¹ is selected from F, G, I, L, P, Q, R, T, and V; X⁷²        is selected from A, D, E, I, M, R, S, T, and V; X⁷³ is selected        from D, E, F, M, N, Q, S T, V, W, and Y; X⁷⁴ is selected from D,        E, F, G, I, L, M, P, R, S, T, and V; X⁷⁵ is selected from F, H,        L, W, and Y; X⁷⁶ is selected from D, E, H, L, N, Q, S, and T;        X⁷⁷ is selected from G, T, Q, and E; X⁷⁸ is selected from I, L,        M, Q, and V; X⁷⁹ is selected from D, E, N, Q, and R; X⁸⁰ is        selected from D, F, I, and L; X⁸¹ is selected from F, I, L, R,        T, W, and Y; and X⁸² is selected from A, F, G, H, I, L, N, P, Q,        S, T, and W.

Aspect 43B. The IL-2Rγc ligand of aspect 42B, wherein X⁷¹ is selectedfrom I, L, and V.

Aspect 44B. The IL-2Rγc ligand of any one of aspects 42B to 43B, whereinX⁷² is selected from A, D, E, I, M, and V.

Aspect 45B. The IL-2Rγc ligand of any one of aspects 42B to 44B, whereinX⁷³ is selected from E, Q, and N.

Aspect 46B. The IL-2Rγc ligand of any one of aspects 42B to 45B, whereinX⁷⁴ is selected from D and E.

Aspect 47B. The IL-2Rγc ligand of any one of aspects 42B to 46B, whereinX⁷⁵ is selected from F, W, and Y.

Aspect 48B. The IL-2Rγc ligand of any one of aspects 42B to 47B, whereinX⁷⁶ is selected from D, E, L, N, and Q.

Aspect 49B. The IL-2Rγc ligand of any one of aspects 42B to 48B, whereinX⁷⁷ is G.

Aspect 50B. The IL-2Rγc ligand of any one of aspects 42B to 49B, whereinX⁷⁸ is selected from I, M, and V.

Aspect 51B. The IL-2Rγc ligand of any one of aspects 42B to 50B, whereinX⁷⁹ is selected from D, E, Q, and R.

Aspect 52B. The IL-2Rγc ligand of any one of aspects 42B to 51B, whereinX⁸⁰ is selected from F, I, and L.

Aspect 53B. The IL-2Rγc ligand of any one of aspects 42B to 52B, whereinX⁸¹ is W.

Aspect 54B. The IL-2Rγc ligand of any one of aspects 42B to 53B, whereinX⁸² is selected from N and Q.

Aspect 55B. The IL-2Rγc ligand of aspect 42B, wherein, X⁷¹ is selectedfrom I, L, and V; X⁷² is selected from A, D, E, I, M, and V; X⁷³ isselected from E, Q, and N; X⁷⁴ is selected from D and E; X⁷⁵ is selectedfrom F, W, and Y; X⁷⁶ is selected from D, E, L, N, and Q; X⁷⁷ is G; X⁷⁸is selected from I, M, and V; X⁷⁹ is selected from D, E, Q, and R; X⁸⁰is selected from F, I, and L; X⁸¹ is W; and X⁸² is selected from N andQ.

Aspect 56B. The IL-2Rγc ligand of aspect 1B, wherein the IL-2Rγc ligandcomprises the amino acid sequence of Formula (5) (SEQ ID NO: 1071) orFormula (5a) (SEQ ID NO: 1072):

—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—  (5)

—X⁷¹—X⁷²—C—X⁷³—X⁷⁴—X⁷⁵—X⁷⁶—X⁷⁷—X⁷⁸—X⁷⁹—X⁸⁰—C—X⁸¹—X⁸²—  (5a)

-   -   wherein, X⁷¹ is selected from an amino acid; X⁷² is selected        from an amino acid; X⁷³ is selected from an amino acid; X⁷⁴ is        selected from an amino acid; X⁷⁵ is selected from an amino acid        comprising a large hydrophobic side chain; X⁷⁶ is selected from        an amino acid; X⁷⁷ is selected from a small hydrophobic side        chain; X⁷⁸ is selected from an amino acid comprising a large        hydrophobic side chain; X⁷⁹ is selected from an amino acid        comprising a basic side chain, an acidic side chain, or a        polar-neutral side chain; X⁸⁰ is selected from an amino acid        comprising a large hydrophobic side chain; X⁸¹ is selected from        an amino acid comprising a large hydrophobic side chain; and X⁸²        is selected from an amino acid.

Aspect 57B. The IL-2Rγc ligand of aspect 56B, wherein, X⁷¹ is selectedfrom an amino acid comprising a large hydrophobic side chain; X⁷² isselected from an amino acid comprising an acidic side chain or a largehydrophobic side chain; X⁷³ is selected from an amino acid comprising anacidic side chain, a hydroxyl-containing side chain, or a polar neutralside chain; X⁷⁴ is selected from an amino acid comprising an acidic sidechain, a hydroxyl-containing side chain, or a large hydrophobic sidechain; X⁷⁵ is selected from an amino acid comprising a large hydrophobicside chain; X⁷⁶ is selected from an amino acid comprising an acidic sidechain, a hydroxyl-containing side chain, or a polar neutral side chain;X⁷⁷ is selected from a small hydrophobic side chain; X⁷⁸ is selectedfrom an amino acid comprising a large hydrophobic side chain; X⁷⁹ isselected from an amino acid comprising a basic side chain, an acidicside chain, or a polar-neutral side chain; X⁸⁰ is selected from an aminoacid comprising a large hydrophobic side chain; X⁸¹ is selected from anamino acid comprising a large hydrophobic side chain; and X⁸² isselected from an amino acid comprising a polar neutral side chain.

Aspect 58B. The IL-2Rγc ligand of any one of aspects 56B to 57B,wherein, X⁷¹ is selected from F, I, L, M, V, Y, and W; X⁷² is selectedfrom D, E, F, I, L, M, V, Y, and W; X⁷³ is selected from D, E, S, T, H,N, Q, S, T, and Y; X⁷⁴ is selected from D, E, S, T, F, I, L, M, V, Y,and W; X⁷⁵ is selected from F, I, L, M, V, Y, and W; X⁷⁶ is selectedfrom D, E, S, T, H, N, Q, S, T, and Y; X⁷⁷ is selected from A, G, P, S,and T; X⁷⁸ is selected from F, I, L, M, V, Y, and W; X⁷⁹ is selectedfrom R, K, H, D, E, H, N, Q, S, T, and Y; X⁸⁰ is selected from F, I, L,M, V, Y, and W; X⁸¹ is selected from F, I, L, M, V, Y, and W; and X⁸² isselected from H, N, Q, S, T, and Y.

Aspect 59B. The IL-2Rγc ligand of aspect 58B, wherein X⁷¹ is selectedfrom I, L, and V.

Aspect 60B. The IL-2Rγc ligand of any one of aspects 58B to 59B, whereinX⁷² is selected from D, E, I, M, and V.

Aspect 61B. The IL-2Rγc ligand of any one of aspects 58B to 60B, whereinX⁷³ is selected from E, N, and Q.

Aspect 62B. The IL-2Rγc ligand of any one of aspects 58B to 61B, whereinX⁷⁴ is selected from D and E.

Aspect 63B. The IL-2Rγc ligand of any one of aspects 58B to 62B, whereinX⁷⁵ is selected from F, W, and Y.

Aspect 64B. The IL-2Rγc ligand of any one of aspects 58B to 63B, whereinX⁷⁶ is selected from D, E, and N.

Aspect 65B. The IL-2Rγc ligand of any one of aspects 58B to 64B, whereinX⁷⁷ is selected from G.

Aspect 66B. The IL-2Rγc ligand of any one of aspects 58B to 65B, whereinX⁷⁸ is selected from I, M, and V.

Aspect 67B. The IL-2Rγc ligand of any one of aspects 58B to 66B, whereinX⁷⁹ is selected from D, E, N, Q, and R.

Aspect 68B. The IL-2Rγc ligand of any one of aspects 58B to 67B, whereinX⁸⁰ is selected from F, I, and L.

Aspect 69B. The IL-2Rγc ligand of any one of aspects 58B to 68B, whereinX⁸¹ is W.

Aspect 70B. The IL-2Rγc ligand of any one of aspects 58B to 69B, whereinX⁸² is selected from N and Q.

Aspect 71B. The IL-2Rγc ligand of aspect 58B, wherein, X⁷¹ is selectedfrom I, L, and V; X⁷² is selected from D, E, I, M, and V; X⁷³ isselected from E, N, and Q; X⁷⁴ is selected from D and E; X⁷⁵ is selectedfrom F, W, and Y; X⁷⁶ is selected from D, E, and N; X⁷⁷ is selected fromG; X⁷⁸ is selected from I, M, and V; X⁷⁹ is selected from D, E, N, Q,and R; X⁸⁰ is selected from F, I, and L; X⁸¹ is W; and X⁸² is selectedfrom N and Q.

Aspect 72B. The IL-2Rγc ligand of aspect 56B, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 213to SEQ ID NO: 233 and SEQ ID NO: 914 to SEQ ID NO: 920.

Aspect 73B. The IL-2Rγc ligand of aspect 72B, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 213to SEQ ID NO: 233 and SEQ ID NO: 914 to SEQ ID NO: 920, wherein theamino acid sequence is terminated with amino acids -G-G- on theN-terminus, on the C-terminus, or on both the N- and C-termini.

Aspect 74B. The IL-2Rγc ligand of aspect 72B, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 213to SEQ ID NO: 233 and SEQ ID NO: 914 to SEQ ID NO: 920, wherein eachamino acid independently comprises one or more of the followingconservative substitutions: amino acids having a small hydrophobic sidechain comprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 75B. The IL-2Rγc ligand of aspect 1B, wherein the IL-2Rγc ligandcomprises the amino acid sequence of Formula (6) (SEQ ID NO: 234) orFormula (6a) (SEQ ID NO: 235):

—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰—X¹⁰¹—  (6)

—X⁹¹—X⁹²—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰—X¹⁰¹—X¹⁰²—X¹⁰³—  (6a)

-   -   wherein, X⁹¹ is selected from C, D, E, and L; X⁹² is selected        from C, L, M, R, S, V, and W; X⁹³ is selected from C, D, F, P,        and R; X⁹⁴ is selected from A, D, L, Q, S, and W; X⁹⁵ is        selected from D, E, F, L, and V; X⁹⁶ is selected from A, D, E,        F, G, K, Q, and S; X⁹⁷ is selected from E, L, M, and W; X⁹⁸ is        selected from G, I, L, W, and Y; X⁹⁹ is selected from E, I, R,        T, and V; X¹⁰⁰ is W; X¹⁰¹ is selected from C, A, I, L, P, and V;        X¹⁰² is selected from C, D, G, H; and X¹⁰³ is selected from C,        D, E, H, S, and T.

Aspect 76B. The IL-2Rγc ligand of aspect 75B, wherein X⁹¹ is selectedfrom D and E.

Aspect 77B. The IL-2Rγc ligand of any one of aspects 75B to 76B, whereinX⁹² is selected from L, M, R, S, V, and W.

Aspect 78B. The IL-2Rγc ligand of any one of aspects 75B to 77B, whereinX⁹³ is selected from D and F.

Aspect 79B. The IL-2Rγc ligand of any one of aspects 75B to 78B, whereinX⁹⁴ is S.

Aspect 80B. The IL-2Rγc ligand of any one of aspects 75B to 79B, whereinX⁹⁵ is selected from D and E.

Aspect 81B. The IL-2Rγc ligand of any one of aspects 75B to 80B, whereinX⁹⁶ is selected from D and E.

Aspect 82B. The IL-2Rγc ligand of any one of aspects 75B to 81B, whereinX⁹⁷ is selected from L, M, and W.

Aspect 83B. The IL-2Rγc ligand of any one of aspects 75B to 82B, whereinX⁹⁸ is G.

Aspect 84B. The IL-2Rγc ligand of any one of aspects 75B to 83B, whereinX⁹⁹ is E.

Aspect 85B. The IL-2Rγc ligand of any one of aspects 75B to 84B, whereinX¹⁰⁰ is W.

Aspect 86B. The IL-2Rγc ligand of any one of aspects 75B to 85B, whereinX¹⁰¹ is selected from I, L, and V.

Aspect 87B. The IL-2Rγc ligand of any one of aspects 75B to 86B, whereinX¹⁰² is selected from D and G.

Aspect 88B. The IL-2Rγc ligand of any one of aspects 75B to 87B, whereinX¹⁰³ is selected from S and T.

Aspect 89B. The IL-2Rγc ligand of aspect 75B, wherein, X⁹¹ is selectedfrom D and E; X⁹² is selected from L, M, R, S, V, and W; X⁹³ is selectedfrom D and F; X⁹⁴ is S; X⁹⁵ is selected from D and E; X⁹⁶ is selectedfrom D and E; X⁹⁷ is selected from L, M, and W; X⁹⁸ is G; X⁹⁹ is E; X¹⁰⁰is W; X¹⁰¹ is selected from I, L, and V; X¹⁰² is selected from D and G;and X¹⁰³ is selected from S and T.

Aspect 90B. The IL-2Rγc ligand of aspect 75B, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 236to SEQ ID NO: 245:

Aspect 91B. The IL-2Rγc ligand of aspect 90B, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 236to SEQ ID NO: 245, wherein the amino acid sequence is terminated withamino acids -G-G- on the N-terminus, on the C-terminus, or on both theN- and C-termini.

Aspect 92B. The IL-2Rγc ligand of aspect 90B, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 236to SEQ ID NO: 245, wherein each amino acid independently comprises oneor more of the following conservative substitutions: amino acids havinga small hydrophobic side chain comprising alanine (A), glycine (G),proline (P), serine (S), or threonine (T); amino acids having ahydroxyl-containing side chain comprising serine (S), threonine (T), ortyrosine (Y); amino acids having an acidic side chain comprisingaspartate (D) or glutamate (E); amino acids having a polar-neutral sidechain comprising histidine (H), asparagine (N), glutamine (Q), serine(S), threonine (T), or tyrosine (Y); amino acids having a basic sidechain comprising arginine (R), lysine (K), or histidine (H); amino acidshaving a large hydrophobic side chain comprising isoleucine (I), leucine(L), methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 93B. The IL-2Rγc ligand of aspect 1B, wherein the IL-2Rγc ligandcomprises the amino acid sequence of Formula (6) (SEQ ID NO: 1075) orFormula (6a) (SEQ ID NO: 1076):

—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰—X¹⁰¹—  (6)

—X⁹¹—X⁹²—X⁹³—X⁹⁴—X⁹⁵—X⁹⁶—X⁹⁷—X⁹⁸—X⁹⁹—X¹⁰⁰—X¹⁰¹—X¹⁰²—X¹⁰³—  (6a)

-   -   wherein, X⁹¹ is selected from an amino acid comprising an acidic        side chain or cysteine; X⁹² is selected from an amino acid; X⁹³        is selected from an amino acid comprising an acidic side chain        or large hydrophobic side chain; X⁹⁴ is selected from an amino        acid; X⁹⁵ is selected from an amino acid; X⁹⁶ is selected from        an amino acid; X⁹⁷ is selected from an amino acid comprising a        large hydrophobic side chain; X⁹⁸ is selected from an amino acid        comprising a small hydrophobic side chain or a large hydrophobic        side chain; X⁹⁹ is selected from an amino acid; X¹⁰⁰ is selected        from an amino acid comprising a large hydrophobic side chain;        X¹⁰¹ is selected from an amino acid comprising a large        hydrophobic side chain; X¹⁰² is selected from an amino acid        comprising a small hydrophobic side chain or an acidic side        chain or cysteine; and X¹⁰³ is selected from an amino acid        comprising an acidic side chain or a hydroxyl-containing side        chain or cysteine.

Aspect 94B. The IL-2Rγc ligand of aspect 93B, wherein, X⁹¹ is selectedfrom an amino acid comprising an acidic side chain; X⁹² is selected froman amino acid; X⁹³ is selected from an amino acid comprising an acidicside chain or large hydrophobic side chain; X⁹⁴ is selected from anamino acid comprising an acidic side chain or a hydroxyl-containing sidechain; X⁹⁵ is selected from an amino acid comprising an acidic sidechain; X⁹⁶ is selected from an amino acid; X⁹⁷ is selected from an aminoacid comprising a large hydrophobic side chain; X⁹⁸ is selected from anamino acid comprising a small hydrophobic side chain or a largehydrophobic side chain; X⁹⁹ is selected from an amino acid comprising anacidic side chain or large hydrophobic side chain; X¹⁰⁰ is selected froman amino acid comprising a large hydrophobic side chain; X¹⁰¹ isselected from an amino acid comprising a large hydrophobic side chain;X¹⁰² is selected from an amino acid comprising a small hydrophobic sidechain or an acidic side chain; and X¹⁰³ is selected from an amino acidcomprising an acidic side chain or a hydroxyl-containing side chain.

Aspect 95B. The IL-2Rγc ligand of any one of aspects 93B to 94B,wherein, X⁹¹ is selected from D and E; X⁹² is selected from an aminoacid; X⁹³ is selected from D, E, F, I, L, M, V, Y, and W; X⁹⁴ isselected from D, E, S, and T; X⁹⁵ is selected from D and E; X⁹⁶ isselected from an amino acid; X⁹⁷ is selected from F, I, L, M, V, Y, andW; X⁹⁸ is selected from A, G, P, S, T, F, I, L, M, V, Y, and W; X⁹⁹ isselected from D, E, F, I, L, M, V, Y, and W; X¹⁰⁰ is selected from F, I,L, M, V, Y, and W; X¹⁰¹ is selected from F, I, L, M, V, Y, and W; X¹⁰²is selected from D, E, A, G, P, S, and T; and X¹⁰³ is selected from D,E, S, and T.

Aspect 96B. The IL-2Rγc ligand of aspect 95B, wherein X⁹¹ is selectedfrom D and E.

Aspect 97B. The IL-2Rγc ligand of any one of aspects 95B to 96B, whereinX⁹² is selected from an amino acid.

Aspect 98B. The IL-2Rγc ligand of any one of aspects 95B to 97B, whereinX⁹³ is selected from D and F.

Aspect 99B. The IL-2Rγc ligand of any one of aspects 95B to 98B, whereinX⁹⁴ is S.

Aspect 100B. The IL-2Rγc ligand of any one of aspects 95B to 99B,wherein X⁹⁵ is selected from D and E.

Aspect 101B. The IL-2Rγc ligand of any one of aspects 95B to 100B,wherein X⁹⁶ is selected from an amino acid.

Aspect 102B. The IL-2Rγc ligand of any one of aspects 95B to 101B,wherein X⁹⁷ is selected from L, M, and W.

Aspect 103B. The IL-2Rγc ligand of any one of aspects 95B to 102B,wherein X⁹⁸ is G.

Aspect 104B. The IL-2Rγc ligand of any one of aspects 95B to 103B,wherein X⁹⁹ is E.

Aspect 105B. The IL-2Rγc ligand of any one of aspects 95B to 104B,wherein X¹⁰⁰ is W.

Aspect 106B. The IL-2Rγc ligand of any one of aspects 95B to 105B,wherein X¹⁰¹ is selected from I, L, and V.

Aspect 107B. The IL-2Rγc ligand of any one of aspects 95B to 106B,wherein X¹⁰² is selected from D and G.

Aspect 108B. The IL-2Rγc ligand of any one of aspects 95B to 107B,wherein X¹⁰³ is selected from S and T.

Aspect 109B. The IL-2Rγc ligand of aspect 95B, wherein, X⁹¹ is selectedfrom D and E; X⁹² is selected from an amino acid; X⁹³ is selected from Dand F; X⁹⁴ is S; X⁹⁵ is selected from D and E; X⁹⁶ is selected from anamino acid; X⁹⁷ is selected from L, M, and W; X⁹⁸ is G; X⁹⁹ is E; X¹⁰⁰is W; X¹⁰¹ is selected from I, L, and V; X¹⁰² is selected from D and G;and X¹⁰³ is selected from S and T.

Aspect 110B. The IL-2Rγc ligand of aspect 1B, wherein the IL-2Rγc ligandcomprises the amino acid sequence of Formula (7) (SEQ ID NO: 1081) orFormula (7a) (SEQ ID NO: 1082):

—X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹¹⁷—X¹¹⁸—  (7)

—X¹¹¹—X¹¹²—X¹¹³—X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹¹⁷—X¹¹⁸—X¹¹⁹—X¹²⁰—X¹²¹—  (7a)

-   -   wherein, X¹¹¹ is selected from D, G, I, and Q; X¹¹² is selected        from D, I, and L; X¹¹³ is selected from G, L, M, Q, R, S, and Y;        X¹¹⁴ is selected from D, E, G, L, S, T, and Y; X¹¹⁵ is selected        from E, L, P, and Q; X¹¹⁶ is selected from D, E, K, L, S, and T;        X¹¹⁷ is selected from D, F, S, and W; X¹¹⁸ is selected from F,        N, W, and Y; X¹¹⁹ is selected from F, I, L, R and W; X¹²⁰ is        selected from A, E, L, and S; and X¹²¹ is selected from H, L, K,        N, Q, and V.

Aspect 111B. The IL-2Rγc ligand of aspect 110B, wherein X¹¹¹ is selectedfrom D and Q.

Aspect 112B. The IL-2Rγc ligand of any one of aspects 110B to 111B,wherein X¹¹² is selected from I and L.

Aspect 113B. The IL-2Rγc ligand of any one of aspects 110B to 112B,wherein X¹¹³ is selected from G, L, M, R, S, and Y.

Aspect 114B. The IL-2Rγc ligand of any one of aspects 110B to 113B,wherein X¹¹⁴ is L.

Aspect 115B. The IL-2Rγc ligand of any one of aspects 110B to 114B,wherein X¹⁵ is selected from E and Q.

Aspect 116B. The IL-2Rγc ligand of any one of aspects 110B to 115B,wherein X¹¹⁶ is selected from D and E.

Aspect 117B. The IL-2Rγc ligand of any one of aspects 110B to 116B,wherein X¹¹⁷ is selected from F and W.

Aspect 118B. The IL-2Rγc ligand of any one of aspects 110B to 117B,wherein X¹¹⁸ is selected from F, W, and Y.

Aspect 119B. The IL-2Rγc ligand of any one of aspects 110B to 118B,wherein X¹¹⁹ is selected from F, I, and L.

Aspect 120B. The IL-2Rγc ligand of any one of aspects 110B to 119B,wherein X¹²⁰ is S.

Aspect 121B. The IL-2Rγc ligand of any one of aspects 110B to 120B,wherein X¹²¹ is selected from N and Q.

Aspect 122B. The IL-2Rγc ligand of aspect 110B, wherein, X¹¹¹ isselected from D and Q; X¹¹² is selected from I and L; X¹¹³ is selectedfrom G, L, M, R, S, and Y; X¹¹⁴ is L; X¹¹⁵ is selected from E and Q;X¹¹⁶ is selected from D and E; X¹¹⁷ is selected from F and W; X¹¹⁸ isselected from F, W, and Y; X¹¹⁹ is selected from F, I, and L; X¹²⁰ is S;and X¹²¹ is selected from N and Q.

Aspect 123B. The IL-2Rγc ligand of aspect 110B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 248 to SEQ ID NO: 254 and SEQ ID NO: 1051 and SEQ ID NO: 921 to SEQID NO: 922.

Aspect 124B. The IL-2Rγc ligand of aspect 123B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 248 to SEQ ID NO: 254 and SEQ ID NO: 1051 and SEQ ID NO: 921 to SEQID NO: 922, wherein the amino acid sequence is terminated with aminoacids -G-G- on the N-terminus, on the C-terminus, or on both the N- andC-termini.

Aspect 125B. The IL-2Rγc ligand of aspect 123B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 248 to SEQ ID NO: 254 and SEQ ID NO: 1051 and SEQ ID NO: 921 to SEQID NO: 922, wherein each amino acid independently comprises one or moreof the following conservative substitutions: amino acids having a smallhydrophobic side chain comprising alanine (A), glycine (G), proline (P),serine (S), or threonine (T); amino acids having a hydroxyl-containingside chain comprising serine (S), threonine (T), or tyrosine (Y); aminoacids having an acidic side chain comprising aspartate (D) or glutamate(E); amino acids having a polar-neutral side chain comprising histidine(H), asparagine (N), glutamine (Q), serine (S), threonine (T), ortyrosine (Y); amino acids having a basic side chain comprising arginine(R), lysine (K), or histidine (H); amino acids having a largehydrophobic side chain comprising isoleucine (I), leucine (L),methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 126B. The IL-2Rγc ligand of aspect 1B, wherein the IL-2Rγc ligandcomprises the amino acid sequence of Formula (7) (SEQ ID NO: 1077) orFormula (7a) (SEQ ID NO: 1078):

—X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹¹⁷—X¹¹⁸—  (7)

—X¹¹¹—X¹¹²—X¹¹³—X¹¹⁴—X¹¹⁵—C—X¹¹⁶—X¹¹⁷—X¹¹⁸—X¹¹⁹—X¹²⁰—X¹²¹—  (7a)

-   -   wherein, X¹¹¹ is selected from an amino acid; X¹¹² is selected        from an amino acid comprising a large hydrophobic side chain or        an acidic side chain; X¹¹³ is selected from an amino acid; X¹¹⁴        is selected from an amino acid comprising an acidic side chain        or a hydroxyl-containing side chain; X¹¹⁵ is selected from an        amino acid; X¹¹⁶ is selected from an amino acid; X¹¹⁷ is        selected from an amino acid comprising a large hydrophobic side        chain; X¹¹⁸ is selected from an amino acid comprising a large        hydrophobic side chain; X¹¹⁹ is selected from an amino acid        comprising a large hydrophobic side chain; X¹²⁰ is selected from        an amino acid; and X¹²¹ is selected from an amino acid.

Aspect 127B. The IL-2Rγc ligand of aspect 125B, wherein, X¹¹¹ isselected from an amino acid; X¹¹² is selected from an amino acidcomprising a large hydrophobic side chain or an acidic side chain; X¹¹³is selected from an amino acid; X¹¹⁴ is selected from an amino acidcomprising an acidic side chain or a hydroxyl-containing side chain;X¹¹⁵ is selected from an amino acid comprising a large hydrophobic sidechain; X¹¹⁶ is selected from an amino acid comprising an acidic sidechain; X¹¹⁷ is selected from an amino acid comprising a largehydrophobic side chain; X¹¹⁸ is selected from an amino acid comprising alarge hydrophobic side chain; X¹¹⁹ is selected from an amino acidcomprising a large hydrophobic side chain; X¹²⁰ is selected from anamino acid; and X¹²¹ is selected from an amino acid comprising apolar-neutral side chain.

Aspect 128B. The IL-2Rγc ligand of any one of aspects 126B to 127B,wherein, X¹¹¹ is selected from an amino acid; X¹¹² is selected from D,E, F, I, L, M, V, Y, and W; X¹¹³ is selected from an amino acid; X¹¹⁴ isselected from D, E, S, T, and Y; X¹¹⁵ is selected from F, I, L, M, V, Y,and W; X¹¹⁶ is selected from D and E; X¹¹⁷ is selected from F, I, L, M,V, Y, and W; X¹¹⁸ is selected from F, I, L, M, V, Y, and W; X¹¹⁹ isselected from F, I, L, M, V, Y, and W; X¹²⁰ is selected from an aminoacid; and X¹²¹ is selected from H, N, Q, S, T, and Y.

Aspect 129B. The IL-2Rγc ligand of aspect 128B, wherein X¹¹¹ is selectedfrom an amino acid.

Aspect 130B. The IL-2Rγc ligand of any one of aspects 128B to 129B,wherein X¹¹² is selected from I and L.

Aspect 131B. The IL-2Rγc ligand of any one of aspects 128B to 130B,wherein X¹¹³ is selected from an amino acid.

Aspect 132B. The IL-2Rγc ligand of any one of aspects 128B to 131B,wherein X¹¹⁴ is selected from D, E, and S.

Aspect 133B. The IL-2Rγc ligand of any one of aspects 128B to 132B,wherein X¹¹⁵ is L.

Aspect 134B. The IL-2Rγc ligand of any one of aspects 128B to 133B,wherein X¹¹⁶ is selected from D and E.

Aspect 135B. The IL-2Rγc ligand of any one of aspects 128B to 134B,wherein X¹¹⁷ is selected from F and W.

Aspect 136B. The IL-2Rγc ligand of any one of aspects 128B to 135B,wherein X¹¹⁸ is selected from F, W and Y.

Aspect 137B. The IL-2Rγc ligand of any one of aspects 128B to 136B,wherein X¹¹⁹ is selected from F, I, and L.

Aspect 138B. The IL-2Rγc ligand of any one of aspects 128B to 137B,wherein X¹²⁰ is selected from an amino acid.

Aspect 139B. The IL-2Rγc ligand of any one of aspects 128B to 138B,wherein X¹²¹ is selected from Q and N.

Aspect 140B. The IL-2Rγc ligand of aspect 128B, wherein, X¹¹¹ isselected from an amino acid; X¹¹² is selected from I and L; X¹¹³ isselected from an amino acid; X¹¹⁴ is selected from D, E, and S; X¹¹⁵ isL; X¹¹⁶ is selected from D and E; X¹¹⁷ is selected from F and W; X¹¹⁸ isselected from F, W and Y; X¹¹⁹ is selected from F, I, and L; X¹²⁰ isselected from an amino acid; and X¹²¹ is selected from Q and N.

Aspect 141B. The IL-2Rγc ligand of aspect 126B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 255 to SEQ ID NO: 267 and SEQ ID NO: 923 to SEQ ID NO: 930.

Aspect 142B. The IL-2Rγc ligand of aspect 141B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 255 to SEQ ID NO: 264 and SEQ ID NO: 923 to SEQ ID NO: 930, whereinthe amino acid sequence is terminated with amino acids -G-G- on theN-terminus, on the C-terminus, or on both the N- and C-termini.

Aspect 143B. The IL-2Rγc ligand of aspect 141B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 255 to SEQ ID NO: 264 and SEQ ID NO: 923 to SEQ ID NO: 930, whereineach amino acid independently comprises one or more of the followingconservative substitutions: amino acids having a small hydrophobic sidechain comprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 144B. The IL-2Rγc ligand of aspect 1B, wherein IL-2Rγc ligandcomprises an amino acid sequence of Formula (8) (SEQ ID NO: 1083):

—C—X¹³¹—X¹³²—X¹³³—X¹³⁴—X¹³⁵—X¹³⁶—X¹³⁷—X¹³⁸—X¹³⁹—X¹⁴⁰—X¹⁴¹—X¹⁴²—C—  (8)

-   -   wherein, X¹³¹ is selected from an amino acid comprising a large        hydrophobic side chain; X¹³² is selected from an amino acid        comprising a large hydrophobic side chain; X¹³³ is selected from        an amino acid comprising a large hydrophobic side chain; X¹³⁴ is        selected from an amino acid comprising a large hydrophobic side        chain; X¹³⁵ is selected from an amino acid comprising a basic        side chain and an acidic or polar neutral side chain; X¹³⁶ is        selected from an amino acid; X¹³⁷ is selected from an amino acid        comprising a small hydrophobic side chain; X¹³⁸ is selected from        an amino acid comprising an acidic or a polar neutral side        chain; X¹³⁹ is selected from an amino acid comprising a large        hydrophobic side chain; X¹⁴⁰ is selected from an amino acid        comprising a small hydrophobic side chain or a        hydroxyl-containing side chain; X¹⁴¹ is selected from an amino        acid comprising a large hydrophobic side chain; and X¹⁴² is        selected from an amino acid comprising a large hydrophobic side        chain.

Aspect 145B. The IL-2Rγc ligand of aspect 144B, wherein, X¹³¹ isselected from F, I, L, M, V, Y, and W; X¹³² is selected from F, I, L, M,V, Y, and W; X¹³³ is selected from F, I, L, M, V, Y, and W; X¹³⁴ isselected from F, I, L, M, V, Y, and W; X¹³⁵ is selected from R, K, H, D,E, N, and Q; X¹³⁶ is selected from an amino acid; X¹³⁷ is selected fromA, G, P, S, and T; X¹³⁸ is selected from D, E, N, and Q; X¹³⁹ isselected from F, I, L, M, V, Y, and W; X¹⁴⁰ is selected from A, G, P, S,and T; X¹⁴¹ is selected from F, I, L, M, V, Y, and W; and X¹⁴² isselected from F, I, L, M, V, Y, and W.

Aspect 146B. The IL-2Rγc ligand of any one of aspects 144B to 145B,wherein, X¹³¹ is selected from G, G, A, E, F, G, L, and Y; X¹³² isselected from I, S, N, L, I, and V; X¹³³ is selected from A, M, L, Y, R,M, A, Y, and I; X¹³⁴ is selected from Y, L, H, T, Y, F, K; X¹³⁵ isselected from R, Q, D, G, P, Y, L, I, K, and E; X¹³⁶ is selected from S,G, T, I, F, Q, R, H, N, and L; X¹³⁷ is selected from G, P, Q, T, D, G,N, and K; X¹³⁸ is selected from E, D, K, F, T; X¹³⁹ is selected from F,R, W, Y, V, L, and A; X¹⁴⁰ is selected from T, W, N, E, D, S, T, and L;X¹⁴¹ is selected from M, W, Y, F, A, L, and I; and X¹⁴² is selected fromI, V, Y, L, V, Y, I, E, and M.

Aspect 147B. The IL-2Rγc ligand of aspect 146B, wherein X¹³¹ is selectedfrom F and Y.

Aspect 148B. The IL-2Rγc ligand of any one of aspects 146B to 147B,wherein X¹³² is selected from I, V, and L.

Aspect 149B. The IL-2Rγc ligand of any one of aspects 146B to 147B,wherein X¹³² is I.

Aspect 150B. The IL-2Rγc ligand of any one of aspects 146B to 149B,wherein X¹³³ is selected from M, L, Y, and I.

Aspect 151B. The IL-2Rγc ligand of any one of aspects 146B to 150B,wherein X¹³⁴ is selected from F, H, and Y.

Aspect 152B. The IL-2Rγc ligand of any one of aspects 146B to 150B,wherein X¹³⁴ is Y.

Aspect 153B. The IL-2Rγc ligand of any one of aspects 146B to 152B,wherein X¹³⁵ is selected from R, K, D, and E.

Aspect 154B. The IL-2Rγc ligand of any one of aspects 146B to 152B,wherein X¹³⁵ is R.

Aspect 155B. The IL-2Rγc ligand of any one of aspects 146B to 154B,wherein X¹³⁶ is selected from an amino acid.

Aspect 156B. The IL-2Rγc ligand of any one of aspects 146B to 155B,wherein X¹³⁷ is G.

Aspect 157B. The IL-2Rγc ligand of any one of aspects 146B to 156B,wherein X¹³⁸ is selected from D and E.

Aspect 158B. The IL-2Rγc ligand of any one of aspects 146B to 156B,wherein X¹³⁸ is E.

Aspect 159B. The IL-2Rγc ligand of any one of aspects 146B to 158B,wherein X¹³⁹ is selected from F, Y, and W.

Aspect 160B. The IL-2Rγc ligand of any one of aspects 146B to 158B,wherein X¹³⁹ is F.

Aspect 161B. The IL-2Rγc ligand of any one of aspects 146B to 160B,wherein X¹⁴⁰ is selected from S and T.

Aspect 162B. The IL-2Rγc ligand of any one of aspects 146B to 161B,wherein X¹⁴¹ is selected from F, I, L, M, V, Y, and W.

Aspect 163B. The IL-2Rγc ligand of any one of aspects 146B to 161B,wherein X¹⁴¹ is Y.

Aspect 164B. The IL-2Rγc ligand of any one of aspects 146B to 163B,wherein X¹⁴² is selected from I, L, M, V, and Y.

Aspect 165B. The IL-2Rγc ligand of aspect 146B, wherein, X¹³¹ isselected from F and Y; X¹³² is I; X¹³³ is selected from M, L, Y, and I;X¹³⁴ is Y; X¹³⁵ is R; X¹³⁶ is selected from an amino acid; X¹³⁷ is G;X¹³⁸ is E; X¹³⁹ is F; X¹⁴⁰ is selected from S and T; X¹⁴¹ is Y; and X¹⁴²is selected from F, I, L, M, V, Y, and W.

Aspect 166B. The IL-2Rγc ligand of aspect 146B, wherein X¹³¹ is F, X¹³²is I, X¹³⁴ is Y, X¹³⁵ is R, X¹³⁷ is G, X¹³⁸ is E, X¹³⁹ is F, and X¹⁴¹ isY.

Aspect 167B. The IL-2Rγc ligand of aspect 144B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 265 to SEQ ID NO: 267 and SEQ ID NO: 932 to SEQ ID NO: 940.

Aspect 168B. The IL-2Rγc ligand of aspect 167B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 265 to SEQ ID NO: 267 and SEQ ID NO: 932 to SEQ ID NO: 940, whereinthe amino acid sequence is terminated with amino acids -G-G- on theN-terminus, on the C-terminus, or on both the N- and C-termini.

Aspect 169B. The IL-2Rγc ligand of aspect 167B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 265 to SEQ ID NO: 267 and SEQ ID NO: 932 to SEQ ID NO: 940, whereineach amino acid independently comprises one or more of the followingconservative substitutions: amino acids having a small hydrophobic sidechain comprising alanine (A), glycine (G), proline (P), serine (S), orthreonine (T); amino acids having a hydroxyl-containing side chaincomprising serine (S), threonine (T), or tyrosine (Y); amino acidshaving an acidic side chain comprising aspartate (D) or glutamate (E);amino acids having a polar-neutral side chain comprising histidine (H),asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine(Y); amino acids having a basic side chain comprising arginine (R),lysine (K), or histidine (H); amino acids having a large hydrophobicside chain comprising isoleucine (I), leucine (L), methionine (M),valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); andamino acids having an aromatic side chain comprising phenylalanine (F),histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 170B. The IL-2Rγc ligand of aspect 1B, wherein IL-2Rγc ligandcomprises the amino acid sequence of Formula (9) (SEQ ID NO: 941) or theamino acid sequence of Formula (9a) (SEQ ID NO: 942):

—X¹⁵⁵—X¹⁵⁶—X¹⁵⁷—X¹⁵⁸—X¹⁵⁹—  (9)

—X¹⁵¹—X¹⁵²—X¹⁵³—X¹⁵⁴—C—X¹⁵⁵—X¹⁵⁶—X¹⁵⁷—X¹⁵⁸—X¹⁵⁹—C—X¹⁶⁰—X¹⁶¹—X¹⁶²—X¹⁶³—  (9a)

-   -   wherein, X¹⁵¹ is selected from an amino acid comprising a small        hydrophobic side chain or a hydroxyl-containing side chain; X¹⁵²        is selected from an amino acid comprising a large hydrophobic        side chain; X¹⁵³ is selected from an amino acid comprising an        acidic or polar neutral side chain; X¹⁵⁴ is selected from an        amino acid comprising a basic side chain; X¹⁵⁵ is selected from        an amino acid comprising a large hydrophobic side chain; X¹⁵⁶ is        selected from an amino acid comprising a small hydrophobic side        chain or a hydroxyl-containing side chain; X¹⁵⁷ is selected from        an amino acid comprising a small hydrophobic side chain; X¹⁵⁸ is        selected from an amino acid comprising a small hydrophobic side        chain or a hydroxyl-containing side chain; X¹⁵⁹ is selected from        an amino acid comprising a small hydrophobic side chain or a        hydroxyl-containing side chain; X¹⁶⁰ is selected from an amino        acid comprising a small hydrophobic side chain or a        hydroxyl-containing side chain; X¹⁶¹ is selected from an amino        acid; X¹⁶² is selected from an amino acid comprising a large        hydrophobic side chain or a basic side chain; and X¹⁶³ is        selected from an amino acid comprising a large hydrophobic side        chain.

Aspect 171B. The IL-2Rγc ligand of aspect 170B, wherein, X¹⁵¹ isselected from A, G, P, S, and T; X¹⁵² is selected from F, I, L, M, V, Y,and W; X¹⁵³ is selected from D, E, N, and Q; X¹⁵⁴ is selected from H, K,and R; X¹⁵⁵ is selected from F, I, L, M, V, Y, and W; X¹⁵⁶ is selectedfrom A, G, P, S, T, and Y; X¹⁵⁷ is selected from A, G, P, S, and T; X¹⁵⁸is selected from A, G, P, S, T, and Y; X¹⁵⁹ is selected from A, G, P, S,T, and Y; X¹⁶⁰ is selected from A, G, P, S, T, and Y; X¹⁶¹ is selectedfrom an amino acid; X¹⁶² is selected from F, I, L, M, V, Y, W, R, K, andH; and X¹⁶³ is selected from F, I, L, M, V, Y, and W.

Aspect 172B. The IL-2Rγc ligand of any one of aspects 170B to 171B,wherein, X¹⁵¹ is selected from K, M, N, and K; X¹⁵² is selected from M,L, and Y; X¹⁵³ is selected from N, Y, and L; X¹⁵⁴ is K; X¹⁵⁵ is selectedfrom A, W, R, Y, and N; X¹⁵⁶ is selected from T, N, and S; X¹⁵⁷ isselected from P and A; X¹⁵⁸ is selected from S, R, F, and L; X¹⁵⁹ isselected from Q, S, E, and T; X¹⁶⁰ is selected from S, Q, and A; X¹⁶¹ isselected from V, S, G, L, and N; X¹⁶² is selected from I, K, R, and V;and X¹⁶³ is selected from F and L.

Aspect 173B. The IL-2Rγc ligand of aspect 172B, wherein X¹⁵¹ is selectedfrom S and T.

Aspect 174B. The IL-2Rγc ligand of any one of aspects 172B to 173B,wherein X¹⁵² is selected from L and M.

Aspect 175B. The IL-2Rγc ligand of any one of aspects 172B to 173B,wherein X¹⁵² is L.

Aspect 176B. The IL-2Rγc ligand of any one of aspects 172B to 175B,wherein X¹⁵³ is N.

Aspect 177B. The IL-2Rγc ligand of any one of aspects 172B to 176B,wherein X¹⁵⁴ is K.

Aspect 178B. The IL-2Rγc ligand of any one of aspects 172B to 177B,wherein X¹⁵⁵ is selected from W and Y.

Aspect 179B. The IL-2Rγc ligand of any one of aspects 172B to 178B,wherein X¹⁵⁶ is selected from S and T.

Aspect 180B. The IL-2Rγc ligand of any one of aspects 172B to 178B,wherein X¹⁵⁶ is S.

Aspect 181B. The IL-2Rγc ligand of any one of aspects 172B to 180B,wherein X¹⁵⁷ is P.

Aspect 182B. The IL-2Rγc ligand of any one of aspects 172B to 181B,wherein X¹⁵⁸ is S.

Aspect 183B. The IL-2Rγc ligand of any one of aspects 172B to 182B,wherein X¹⁵⁹ is selected from S and T.

Aspect 184B. The IL-2Rγc ligand of any one of aspects 172B to 182B,wherein X¹⁵⁹ is S.

Aspect 185B. The IL-2Rγc ligand of any one of aspects 172B to 183B,wherein X¹⁶⁰ is S.

Aspect 186B. The IL-2Rγc ligand of any one of aspects 172B to 184B,wherein X¹⁶¹ is selected from an amino acid.

Aspect 187B. The IL-2Rγc ligand of any one of aspects 172B to 185B,wherein X¹⁶² is selected from I, V, R, and K.

Aspect 188B. The IL-2Rγc ligand of any one of aspects 172B to 185B,wherein X¹⁶² is selected from I and V.

Aspect 189B. The IL-2Rγc ligand of any one of aspects 172B to 185B,wherein X¹⁶² is selected from R and K.

Aspect 190B. The IL-2Rγc ligand of any one of aspects 172B to 186B,wherein X¹⁶³ is selected from F and L.

Aspect 191B. The IL-2Rγc ligand of any one of aspects 172B to 186B,wherein X¹⁶³ is L.

Aspect 192B. The IL-2Rγc ligand of aspect 172B, wherein, X¹⁵¹ isselected from S and T; X¹⁵² is L; X¹⁵³ is N; X¹⁵⁴ is K; X¹⁵⁵ is selectedfrom Wand Y; X¹⁵⁶ is S; X¹⁵⁷ is P; X¹⁵⁸ is S; X¹⁵⁹ is S; X¹⁶⁰ is S T;X¹⁶¹ is selected from an amino acid; X¹⁶² is I; and X¹⁶³ is F.

Aspect 193B. The IL-2Rγc ligand of aspect 172B, wherein X¹⁵² is L, X¹⁵³is N, X¹⁵⁴ is K, X¹⁵⁶ is S, X¹⁵⁷ is P, X¹⁵⁸ is S, X¹⁵⁹ is S, X¹⁶⁰ is S,X¹⁶² is I, and X¹⁶³ is F.

Aspect 194B. The IL-2Rγc ligand of aspect 170B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 943 to SEQ ID NO: 948:

Aspect 195B. The IL-2Rγc ligand of aspect 194B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 943 to SEQ ID NO: 948, wherein the amino acid sequence is terminatedwith amino acids -G-G- on the N-terminus, on the C-terminus, or on boththe N- and C-termini.

Aspect 196B. The IL-2Rγc ligand of aspect 194B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 943 to SEQ ID NO: 948, wherein each amino acid independentlycomprises one or more of the following conservative substitutions: aminoacids having a small hydrophobic side chain comprising alanine (A),glycine (G), proline (P), serine (S), or threonine (T); amino acidshaving a hydroxyl-containing side chain comprising serine (S), threonine(T), or tyrosine (Y); amino acids having an acidic side chain comprisingaspartate (D) or glutamate (E); amino acids having a polar-neutral sidechain comprising histidine (H), asparagine (N), glutamine (Q), serine(S), threonine (T), or tyrosine (Y); amino acids having a basic sidechain comprising arginine (R), lysine (K), or histidine (H); amino acidshaving a large hydrophobic side chain comprising isoleucine (I), leucine(L), methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 197B. The IL-2Rγc ligand of aspect 1B, wherein the IL-2Rγc ligandcomprises the amino acid sequence of Formula (12) (SEQ ID NO: 949):

—X¹⁷¹—X¹⁷²—X¹⁷³—X¹⁷⁴—X¹⁷⁵—C—X¹⁷⁶—X¹⁷⁷—X¹⁷⁸—X¹⁷⁹—X¹⁸⁰—X¹⁸¹—X¹⁸²—X¹⁸³—C—X¹⁸⁴—X¹⁸⁵—X¹⁸⁶—X¹⁸⁷—X¹⁸⁸—  (12)

wherein, X¹⁷¹ is selected from an amino acid comprising a basic sidechain; X¹⁷² is selected from an amino acid comprising ahydroxyl-containing side chain; X¹⁷³ is selected from an amino acidcomprising an acidic side chain or a large hydrophobic side chain; X¹⁷⁴is selected from an amino acid comprising a large hydrophobic sidechain; X¹⁷⁵ is selected from an amino acid comprising an acidic sidechain or a large hydrophobic side chain; X¹⁷⁶ is selected from an aminoacid comprising an acidic side chain or a polar/neutral side chain; X¹⁷⁷is selected from an amino acid comprising an acidic side chain; X¹⁷⁸ isselected from an amino acid comprising a large hydrophobic side chain oran aromatic side chain; X¹⁷⁹ is selected from an amino acid comprisingan acidic side chain or a polar/neutral side chain; X¹⁸⁰ is G; X¹⁸¹ isV; X¹⁸² is E; X¹⁸³ is L; X¹⁸⁴ is W; X¹⁸⁵ is selected from an amino acidcomprising a large hydrophobic side chain; X¹⁸⁶ is E; X¹⁸⁷ is selectedfrom an amino acid; and X¹⁸⁸ is selected from an amino acid comprisingan acidic side chain.

Aspect 198B. The IL-2Rγc ligand of aspect 196B, wherein, X¹⁷¹ isselected from H, K, and R; X¹⁷² is selected from S, T, and Y; X¹⁷³ isselected from D, E, F, I, and V; X¹⁷⁴ is selected from I and V; X¹⁷⁵ isselected from E, I, L, M, and V; X¹⁷⁶ is selected from D, E, and Q; X¹⁷⁷is selected from D and E; X¹⁷⁸ is selected from F and W; X¹⁷⁹ isselected from D, E, N, and Q; X¹⁸⁰ is G; X¹⁸¹ is V; X¹⁸² is selectedfrom D and E; X¹⁸³ is L; X¹⁸⁴ is W; X¹⁸⁵ is selected from I, L, Q, andV; X¹⁸⁶ is selected from D and E; X¹⁸⁷ is selected from A, D, E, F, G,I, M, N, P, Q, R, S, T, V, W, and Y; and X¹⁸⁸ is selected from D, E, N,and Q.

Aspect 199B. The IL-2Rγc ligand of aspect 198B, wherein X¹⁷¹ is selectedfrom H, K, and R.

Aspect 200B. The IL-2Rγc ligand of any one of aspects 198B to 199B,wherein X¹⁷² is selected from S, T, and Y.

Aspect 201B. The IL-2Rγc ligand of any one of aspects 198B to 200B,wherein X¹⁷³ is selected from D, E, F, I, L, M, V, W, and Y.

Aspect 202B. The IL-2Rγc ligand of any one of aspects 198B to 200B,wherein X¹⁷³ is selected from D and E.

Aspect 203B. The IL-2Rγc ligand of any one of aspects 198B to 200B,wherein X¹⁷³ is selected from F, I, L, M, V, W, and Y.

Aspect 204B. The IL-2Rγc ligand of any one of aspects 198B to 203B,wherein X¹⁷⁴ is selected from F, I, L, M, V, W, and Y.

Aspect 205B. The IL-2Rγc ligand of any one of aspects 198B to 203B,wherein X¹⁷⁴ is V.

Aspect 206B. The IL-2Rγc ligand of any one of aspects 198B to 205B,wherein X¹⁷⁵ is selected from D, E, F, I, L, M, V, W, and Y.

Aspect 207B. The IL-2Rγc ligand of any one of aspects 198B to 205B,wherein X¹⁷⁵ is selected from D and E.

Aspect 208B. The IL-2Rγc ligand of any one of aspects 198B to 205B,wherein X¹⁷⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 209B. The IL-2Rγc ligand of any one of aspects 198B to 208B,wherein X¹⁷⁶ is selected from D, E, H, N, Q, S, T, and Y.

Aspect 210B. The IL-2Rγc ligand of any one of aspects 198B to 208B,wherein X¹⁷⁶ is selected from E and Q.

Aspect 211B. The IL-2Rγc ligand of any one of aspects 198B to 210B,wherein X¹⁷⁷ is selected from D and E.

Aspect 212B. The IL-2Rγc ligand ofany one of aspects 198B to 211B,wherein X¹⁷⁸ is selected from F, H, I, L, M, V, W, and Y.

Aspect 213B. The IL-2Rγc ligand of any one of aspects 198B to 211B,wherein X¹⁷⁸ is selected from F, H, W, and Y.

Aspect 214B. The IL-2Rγc ligand of any one of aspects 198B to 211B,wherein X¹⁷⁸ is W.

Aspect 215B. The IL-2Rγc ligand of any one of aspects 198B to 214B,wherein X¹⁷⁹ is selected from D, E, H, N, Q, S, T, and Y.

Aspect 216B. The IL-2Rγc ligand of any one of aspects 198B to 214B,wherein X¹⁷⁹ is selected from D, E, and Q.

Aspect 217B. The IL-2Rγc ligand of any one of aspects 198B to 216B,wherein X¹⁸⁰ is G.

Aspect 218B. The IL-2Rγc ligand of any one of aspects 198B to 217B,wherein X¹⁸¹ is V.

Aspect 219B. The IL-2Rγc ligand of any one of aspects 198B to 218B,wherein X¹⁸² is E.

Aspect 220B. The IL-2Rγc ligand of any one of aspects 198B to 219B,wherein X¹⁸³ is L.

Aspect 221B. The IL-2Rγc ligand of any one of aspects 198B to 220B,wherein X¹⁸⁴ is W.

Aspect 222B. The IL-2Rγc ligand of any one of aspects 198B to 221B,wherein X¹⁸⁵ is selected from F, I, L, M, V, W, and Y.

Aspect 223B. The IL-2Rγc ligand of any one of aspects 198B to 221B,wherein X¹⁸⁵ is L.

Aspect 224B. The IL-2Rγc ligand of any one of aspects 198B to 223B,wherein X¹⁸⁶ is E.

Aspect 225B. The IL-2Rγc ligand of any one of aspects 198B to 224B,wherein X¹⁸⁷ is selected from an amino acid.

Aspect 226B. The IL-2Rγc ligand of any one of aspects 198B to 225B,wherein X¹⁸⁸ is selected from D and E.

Aspect 227B. The IL-2Rγc ligand of aspect 198B, wherein, X¹⁷¹ isselected from H, K, and R; X¹⁷² is selected from S, T, and Y; X¹⁷³ isselected from D, E, F, I, L, M, V, W, and Y; X¹⁷⁴ is selected from F, I,L, M, V, W, and Y; X¹⁷⁵ is selected from D, E, F, I, L, M, V, W, and Y;X¹⁷⁶ is selected from D, E, H, N, Q, S, T, and Y; X¹⁷⁷ is selected fromD and E; X¹⁷⁸ is selected from F, H, I, L, M, V, W, and Y; X¹⁷⁹ isselected from D, E, H, N, Q, S, T, and Y; X¹⁸⁰ is G; X¹⁸¹ is V; X¹⁸² isE; X¹⁸³ is L; X¹⁸⁴ is selected from W; X¹⁸⁵ is selected from F, I, L, M,V, W, and Y; X¹⁸⁶ is E; X¹⁸⁷ is selected from an amino acid; and X¹⁸⁸ isselected from D and E.

Aspect 228B. The IL-2Rγc ligand of aspect 198B, wherein, X¹⁷¹ isselected from H, K, and R; X¹⁷² is selected from S, T, and Y; X¹⁷³ isselected from D, E, F, I, L, M, V, W, and Y; X¹⁷⁴ is V; X¹⁷⁵ is selectedfrom D, E, F, I, L, M, V, W, and Y; X¹⁷⁶ is selected from D, E, H, N, Q,S, T, and Y; X¹⁷⁶ is selected from E and Q; X¹⁷⁷ is selected from D andE; X¹⁷⁸ is W; X¹⁷⁹ is selected from D, E, and Q; X¹⁸⁰ is G; X¹⁸¹ is V;X¹⁸² is E; X¹⁸³ is L; X¹⁸⁴ isW; X¹⁸⁵ is selected from F, I, L, M, V, W,and Y; X¹⁸⁶ is E; X¹⁸⁷ is selected from an amino acid; and X¹⁸⁸ isselected from D and E.

Aspect 229B. The IL-2Rγc ligand of aspect 196B, wherein IL-2Rγc ligandcomprises the amino acid sequence any one of SEQ ID NO: 950 to SEQ IDNO: 1027.

Aspect 230B. The IL-2Rγc ligand of aspect 229B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 950 to SEQ ID NO: 1027, wherein the amino acid sequence isterminated with amino acids -G-G- on the N-terminus, on the C-terminus,or on both the N- and C-termini.

Aspect 231B. The IL-2Rγc ligand of aspect 229B, wherein the IL-2Rγcligand comprises an amino acid sequence selected from any one of SEQ IDNO: 950 to SEQ ID NO: 1027, wherein each amino acid independentlycomprises one or more of the following conservative substitutions: aminoacids having a small hydrophobic side chain comprising alanine (A),glycine (G), proline (P), serine (S), or threonine (T); amino acidshaving a hydroxyl-containing side chain comprising serine (S), threonine(T), or tyrosine (Y); amino acids having an acidic side chain comprisingaspartate (D) or glutamate (E); amino acids having a polar-neutral sidechain comprising histidine (H), asparagine (N), glutamine (Q), serine(S), threonine (T), or tyrosine (Y); amino acids having a basic sidechain comprising arginine (R), lysine (K), or histidine (H); amino acidshaving a large hydrophobic side chain comprising isoleucine (I), leucine(L), methionine (M), valine (V), phenylalanine (F), tyrosine (Y), ortryptophan (W); and amino acids having an aromatic side chain comprisingphenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).

Aspect 232B. The IL-2Rγc ligand of aspect 1B, wherein the IL-2Rγc ligandcomprises an amino acid sequence selected from any one of SEQ ID NO: 194to SEQ ID NO: 267 and SEQ ID NO: 904 to SEQ ID NO: 1027 and SEQ ID NOS1065-1082.

Aspect 233B. The IL-2Rγc ligand of any one of aspects 1B to 232B,wherein the IL-2Rγc ligand does not comprise the amino acid sequence ofSEQ ID NO: 375 and to SEQ ID NO: 376.

Aspect 234B. A compound comprising at least one IL-2Rγc ligand of anyone of aspects 1B to 233B.

Aspect 235B. The compound of aspect 234B, wherein the compound furthercomprises at least one IL-2Rβ ligand selected from any one of SEQ ID NO:1 to SEQ ID NO: 193, SEQ ID NO. 578 to SEQ ID NO: 903, and SEQ ID NO:1028 to SEQ ID NO: 1043, and SEQ ID NOS 1052-1064 and 1084.

Aspect 236B. The compound of any one of aspects 234B to 235B, whereinthe compound comprises a least one IL-2Rγc ligand.

Aspect 237B. The compound of any one of aspects 234B to 235B, whereinthe compound comprises a linker, wherein the linker couples the at leastone IL-2Rγc ligand, at least one other IL-2Rγc ligand, at least oneIL-2Rβ ligand, and/or a least one IL-2Rγc ligand.

Aspect 238B. The compound of any one of aspects 234B to 235B, whereinthe compound comprises an IL-2Rγc ligand, a linker, and an IL-2Rβligand.

Aspect 239B. The compound of aspect 238B, wherein the linker comprises apeptide linker.

Aspect 240B. The compound of any one of aspects 238B to 239B, whereinthe C-terminus of the IL-2Rγc ligand is covalently bound to the linkerand the C-terminus of the IL-2Rβ ligand is bound to the linker.

Aspect 241B. The compound of any one of aspects 238B to 239B, whereinthe N-terminus of the IL-2Rγc ligand is covalently bound to the linkerand the C-terminus of the IL-2Rβ ligand is bound to the linker.

Aspect 242B. The compound of any one of aspects 238B to 239B, whereinthe C-terminus of the IL-2Rγc ligand is covalently bound to the linkerand the N-terminus of the IL-2Rβ ligand is bound to the linker.

Aspect 243B. The compound of any one of aspects 238B to 239B, whereinthe N-terminus of the IL-2Rγc ligand is covalently bound to the linkerand the N-terminus of the IL-2Rβ ligand is bound to the linker.

Aspect 244B. The compound of any one of aspects 234B to 243B, whereinthe compound is selected from a peptide, a conjugate, a fusion protein,and a single chain peptide.

Aspect 245B. The compound of any one of aspects 234B to 244B, whereinthe compound comprises at least one moiety configured to modify aproperty of the conjugate.

Aspect 246B. The compound of aspect 245B, wherein the property isselected from aqueous solubility, polarity, lipophilicity,pharmacokinetic profile, targeting, bioavailability, pH-dependentbinding, bioactivity, pharmacodynamics, cellular activity, metabolism,efficacy, caging (reversible incapacitation), and a combination of anyof the foregoing.

Aspect 247B. The compound of any one of aspects 245B to 246B, whereinthe at least one moiety comprises a small molecule, a polymer, apeptide, or an antibody.

Aspect 248B. The compound of any one of aspects 234B to 247B, comprisinga pharmacokinetic moiety.

Aspect 249B. The compound of aspect 248B, wherein the pharmacokineticmoiety comprises a polyethylene glycol.

Aspect 250B. The compound of any one of aspects 234B to 249B, comprisinga tumor-targeting moiety.

Aspect 251B. The compound of aspect 250B, wherein the tumor-targetingmoiety comprises a tumor-specific antibody, a tumor-specific antibodyfragment, a tumor-specific protein, or a tumor-specific peptide.

Aspect 252B. The compound of any one of aspects 234B to 251B, comprisingan immune cell-targeting moiety.

Aspect 253B. The compound of any one of aspects 234B to 252B, whereinthe compound is an IL-2R agonist.

Aspect 254B. The compound of any one of aspects 234B to 253B, whereinthe compound is an IL-2R antagonist.

Aspect 255B. The compound of any one of aspects 234B to 254B, whereinthe compound comprises a fusion protein, wherein the IL-2Rα ligand isbound to a fusion partner.

Aspect 256B. The compound of aspect 255B, wherein the fusion proteinpartner comprises an IgG molecule, an IgG FAb fragment, or an Fcfragment,

Aspect 257B. The compound of any one of aspects 255B to 256B, whereinthe protein fusion partner comprises an IL-2, a variant of IL-2, amutant of IL-2, or an IL-2R agonist.

Aspect 258B. The compound of any one of aspects 234B to 257B, whereinthe compound comprises a label.

Aspect 259B. The compound of aspect 258B, wherein the label is selectedfrom a radioisotope, a fluorophore, or a combination thereof.

Aspect 260B. The compound of any one of aspects 234B to 259B, whereinthe compound comprises a cage to protect peripheral tissues fromtoxicity of IL-2R activation.

Aspect 261B. The compound of any one of aspects 234B to 260B, whereinthe compound comprises a moiety configured to target IL-2R-directedimmuno-stimulation of the effector immune cells in the tumor.

Aspect 262B. The compound of any one of aspects 234B to 261B, whereinthe compound comprises a cleavable moiety.

Aspect 263B. The compound of any one of aspects 234B to 262B, whereinthe compound comprises a moiety that is toxic to cells expressing highlevels of the IL-2Rγc subunit.

Aspect 264B. The compound of aspect 263B, wherein the cells expressinghigh levels of the IL-2Rγc subunit comprise cancer cells.

Aspect 265B. The compound of any one of aspects 234B to 264B, whereinthe compound comprises an imaging agent, a diagnostic agent, a targetingagent, a therapeutic agent, or a combination of any of the foregoing.

Aspect 266B. The compound of any one of aspects 234B to 265B, whereinthe compound comprises a moiety configured to target IL-2R-directedimmuno-stimulation of effector immune cells in a tumor.

Aspect 267B. A pharmaceutical composition comprising; an IL-2Rγc ligandof any one of aspects 1B to 233B; a compound of any one of aspects 234Bto 266B; or a combination thereof.

Aspect 268B. The pharmaceutical composition of aspect 267B, furthercomprising: an IL-2Rβ ligand selected from any one of SEQ ID NO: 1 toSEQ ID NO: 193, SEQ ID NO: 578 to SEQ ID NO: 903, and SEQ ID NO: 1028 toSEQ ID NO: 1043, and SEQ ID NOS 1052-1064 and 1084; a compoundcomprising an IL-2Rβ ligand selected from any one of SEQ ID NO: 1 to SEQID NO: 193, SEQ ID NO: 578 to SEQ ID NO: 903, and SEQ ID NO: 1028 to SEQID NO: 1043, and SEQ ID NOS 1052-1064 and 1084; or a combinationthereof.

Aspect 269B. A method of treating cancer in a patient, comprisingadministering to a patient in need of such treatment, a therapeuticallyeffective amount of the pharmaceutical composition of any one of aspects267B to 268B.

Aspect 270B. The method of aspect 269B, wherein the cancer comprises asolid tumor.

Aspect 271B. A method of treating an autoimmune disease in a patient,comprising administering to a patient in need of such treatment, atherapeutically effective amount of the pharmaceutical composition ofany one of aspects 267B to 268B.

Aspect 272B. A method of screening compounds for IL-2Rγc activity,comprising: contacting a cell with, the IL-2Rγc ligand of any one ofaspects 1B to 233B; the compound of any one of aspects 234B to 266B; ora combination of any of the foregoing; wherein the cell expresses theIL-2Rγc subunit; and contacting the cell with a test compound; anddetermining the activity of the test compound.

Aspect 273B. A method of activating the human IL-2 receptor, comprisingcontacting a cell expressing the human IL-2 receptor in vivo with acompound comprising: the IL-2Rγc ligand of any one of aspects 1B to 233Band an IL-2Rβ ligand selected from any one of SEQ ID NO: 1 to SEQ ID NO:193, SEQ ID NO: 578 to SEQ ID NO: 903, and SEQ ID NO: 1028 to SEQ ID NO:1043, and SEQ ID NOS 1052-1064 and 1084, or a compound of any one ofaspects 234B to 266B.

Aspect 274B. A method of activating the human IL-2 receptor in apatient, comprising contacting a cell expressing the human IL-2 receptorin vivo with a compound comprising: the IL-2Rγc ligand of any one ofaspects 1B to 233B and an IL-2Rβ ligand selected from any one of SEQ IDNO: 1 to SEQ ID NO: 193, SEQ ID NO: 578 to SEQ ID NO: 903, and SEQ IDNO: 1028 to SEQ ID NO: 1043, and SEQ ID NOS 1052-1064 and 1084, or acompound of any one of aspects 234B to 266B.

Aspect 275B. A method of treating a disease in a patient, wherein theIL-2 receptor signaling pathway is associated with the etiology of thedisease, comprising administering to a patient in need of such treatmenta therapeutically effective amount of a compound comprising the IL-2Rγcligand of any one of aspects 1B to 233B, or a compound of any one ofaspects 234B to 266B.

Aspect 276B. A method of treating a disease in a patient, whereinactivation of the IL-2 receptor is effective in treating the disease,comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound comprising the IL-2Rγcligand of any one of aspects 1B to 233B, or a compound of any one ofaspects 234B to 266B.

Aspect 277B. A method of treating a disease in a patient, whereininhibition of the IL-2 receptor is effective in treating the disease,comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound comprising the IL-2Rγcligand of any one of aspects 1B to 233B, or a compound of any one ofaspects 234B to 266B.

Aspect 278B. A method of treating a disease in a patient, wherein cellsexpressing the IL-2Rγc subunit are associated with the etiology of thedisease, comprising administering to a patient in need of such treatmenta therapeutically effective amount of a compound comprising the IL-2Rγcligand of any one of aspects 1B to 233B, or a compound of any one ofaspects 234B to 266B.

Aspect 279B. A method of treating a disease in a patient, whereinactivation of IL-2R is effective in treating the disease, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound comprising the IL-2Rγc ligand of any oneof aspects 1B to 233B, or a compound of any one of aspects 234B to 266B.

Aspect 280B. A method of treating a disease in a patient, whereininhibiting IL-2R is effective in treating the disease, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound comprising the IL-2Rγc ligand of any oneof aspects 1B to 233B, or a compound of any one of aspects 234B to 266B.

Aspect 281B. A method of treating a disease in a patient, whereinreducing the sensitivity of Treg cells to IL-2 is effective in treatingthe disease, comprising administering to a patient in need of suchtreatment a therapeutically effective amount of a compound comprisingthe IL-2Rγc ligand of any one of aspects 1B to 233B, or a compound ofany one of aspects 234B to 266B.

Aspect 282B. A method of imaging cells expressing the IL-2Rγc subunitcomprising administering to a patient an effective amount of a compoundcomprising the IL-2Rγc ligand of any one of aspects 1B to 233B, or acompound of any one of aspects 234B to 266B.

Aspect 283B. A method of diagnosing a disease in a patient wherein thedisease is associated with cells expressing the IL-2Rγc subunitcomprising: administering to a patient an effective amount of a compoundcomprising the IL-2Rγc ligand of any one of aspects 1B to 233B, or acompound of any one of aspects 234B to 266B; and determining abiodistribution of the compound comprising the IL-2Rγc ligand of any oneof aspects 1B to 233B, or a compound of any one of aspects 234B to 266B.

Aspect 284B. A method of treating a disease in a patient, comprising:contacting a biological sample from a patient with an IL-2Rγc ligand ofany one of aspects 1B to 233B or a compound comprising an IL-2Rγc ligandof any one of aspects 1B to 233B; determining at least one propertyassociated with binding of the IL-2Rγc ligand to cells of the biologicalsample; and administering to the patient having the disease a compoundcomprising an IL-2Rγc ligand of any one of aspects 1B to 233B based onthe at least one determined property.

Aspect 285B. The method of aspect 284B, wherein the at least oneproperty comprises: an expression level of the IL-2Rγc subunit in cellsof the biological sample; a characterization of cells of the biologicalsample expressing the IL-2Rγc subunit; and/or a binding affinity (IC₅₀)of cells of the biological sample expressing the IL-2Rγc subunit.

Aspect 286B. A method of targeting a compound to cells expressing theIL-2Rγc subunit comprising administering to a patient an effectiveamount of a compound comprising: the IL-2Rγc ligand of any one ofaspects 1B to 233B; and a targeting moiety.

Aspect 287B. A method of delivering a cytotoxic compound to cellsexpressing the IL-2Rγc subunit comprising administering to a patient aneffective amount of a compound comprising: an IL-2Rγc ligand of any oneof aspects 1B to 233B; and cytotoxic moiety.

Aspect 288B. A binding site of the IL-2Rγc subunit, wherein, the groupof IL-2Rγc ligands having amino acid sequences of SEQ ID NO: 194-210,904-913, 211-233, 914-920, 234-245, 246-254, 921-922, 265-267, 932-940,and 1065-1082, competitively bind to the binding site with each of theother IL-2Rγc ligands within the group; an IL-2Rγc ligand having aminoacid sequence of SEQ ID NO: 948 does not compete for binding to thebinding site with the group of IL-2Rγc ligands; and IL-2 does notcompete for binding to the binding site with the group of IL-2Rγcligands.

Aspect 289B. The binding site of aspect 288B, wherein each IL-2Rγcligand of the group of IL-2Rγc ligands has a binding affinity (IC₅₀) tothe IL-2Rγc subunit of less than 100 μM.

Aspect 290B. The binding site of any one of aspects 288B to 289B,wherein each IL-2Rγc ligand of the group of IL-2Rγc ligands has abinding affinity (IC₅₀) to the IL-2Rβ subunit of greater than 100 μM.

Aspect 291B. The binding site of any one of aspects 288B to 290B,wherein an IL-2Rβ ligand having the amino acid sequence of SEQ ID NO: 58does not compete for binding to the binding site with the group ofIL-2Rγc ligands.

Aspect 292B. The binding site of any one of aspects 288B to 291B,wherein the group of IL-2Rγc ligands consists of peptides having theamino acid sequence of SEQ ID NOS: 198, 202, 224, 236, 248, and 1051.

Finally, it should be noted that there are alternative ways ofimplementing the embodiments disclosed herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive,and the claims are not to be limited to the details given herein but maybe modified within the scope and equivalents thereof.

What is claimed is:
 1. An IL-2Rγc ligand comprising an amino acidsequence:—X¹⁷⁴—X¹⁷⁵—C—X¹⁷⁶—X¹⁷⁷—X¹⁷⁸—X¹⁷⁹—X¹⁸⁰—X¹⁸¹—X¹⁸²—X¹⁸³—C—X¹⁸⁴—X¹⁸⁵—wherein, X¹⁷⁴ is selected from F, I, L, M, V, W, and Y; X¹⁷⁵ is selectedfrom D, E, F, I, L, M, V, W, and Y; X¹⁷⁶ is selected from D, E, H, N, Q,S, T, and Y; X¹⁷⁷ is selected from D and E; X¹⁷⁸ is selected from F, H,I, L, M, V, W, and Y; X¹⁷⁹ is selected from an amino acid comprising anacidic side chain or a polar/neutral side chain; X¹⁸⁰ is G; X¹⁸¹ is V;X¹⁸² is E; X¹⁸³ is L; X¹⁸⁴ is W; and X¹⁸⁵ is selected from F, I, L, M,V, W, and Y.
 2. The IL-2Rγc ligand of claim 1, wherein X¹⁷⁴ is V.
 3. TheIL-2Rγc ligand of claim 1, wherein X¹⁷⁵ is selected from D and E.
 4. TheIL-2Rγc ligand of claim 1, wherein X¹⁷⁵ is selected from F, I, L, M, V,W, and Y.
 5. The IL-2Rγc ligand of claim 1, wherein X¹⁷⁶ is selectedfrom E and Q.
 6. The IL-2Rγc ligand of claim 1, wherein X¹⁷⁹ is selectedfrom D, E, H, N, Q, S, T, and Y.
 7. The IL-2Rγc ligand of claim 1,wherein X¹⁷⁸ is selected from F, H, I, L, M, V, W, and Y.
 8. The IL-2Rγcligand of claim 1, wherein X¹⁷⁸ is selected from F, H, W, and Y.
 9. TheIL-2Rγc ligand of claim 1, wherein X¹⁷⁸ is W.
 10. The IL-2Rγc ligand ofclaim 1, wherein X¹⁷⁹ is selected from D, E, and Q.
 11. The IL-2Rγcligand of claim 1, wherein X¹⁸⁵ is L.
 12. The IL-2Rγc ligand of claim 1,wherein, X¹⁷⁴ is selected from I and V; X¹⁷⁵ is selected from E, I, L,M, and V; X¹⁷⁶ is selected from D, E, and Q; X¹⁷⁷ is selected from D andE; X¹⁷⁸ is selected from F and W; X¹⁷⁹ is selected from D, E, and Q;X¹⁸⁰ is G; X¹⁸¹ is V; X¹⁸² is E; X¹⁸³ is L; X¹⁸⁴ is W; and X¹⁸⁵ isselected from I, L, and V.
 13. The IL-2Rγc ligand of claim 1, wherein,X¹⁷⁴ is V; X¹⁷⁵ is selected from D, E, F, I, L, M, V, W, and Y; X¹⁷⁶ isselected from D, E, H, N, Q, S, T, and Y; X¹⁷⁷ is selected from D and E;X¹⁷⁸ is W; X¹⁷⁹ is selected from D, E, and Q; X¹⁸⁰ is G; X¹⁸¹ is V; X¹⁸²is E; X¹⁸³ is L; X¹⁸⁴ is W; and X¹⁸⁵ is selected from F, I, L, M, V, W,and Y.
 14. A compound comprising an IL-2Rγc ligand of claim
 1. 15. Thecompound of claim 14, wherein the compound is selected from a polymer,an antibody, a conjugate, and a fusion protein.
 16. The compound ofclaim 15, wherein, the fusion protein comprises an IgG molecule, an IgGFab fragment, or an Fc fragment.
 17. The compound of claim 14, whereinthe compound comprises an IL-2Rα ligand, an IL-2Rβ ligand, or both anIL-2Rα ligand and an IL-2Rβ ligand.
 18. The compound of claim 14,wherein the compound comprises a tumor-targeting moiety selected from, atumor-specific antibody, a tumor-specific antibody fragment, atumor-specific protein, a tumor-specific peptide, a non-peptidyl tumorcell ligand, or a combination of any of the foregoing.
 19. The compoundof claim 14, wherein the compound comprises an immune cell-targetingmoiety selected from an immune cell-specific antibody, an immunecell-specific antibody fragment, an immune cell-specific protein, animmune cell-specific peptide, a non-peptidyl immune cell-ligand, or acombination of any of the foregoing.
 20. A pharmaceutical compositioncomprising the IL-2Rγc ligand of claim
 1. 21. A pharmaceuticalcomposition comprising the compound of claim 14.